Compounds for degrading tau protein aggregates and uses thereof

ABSTRACT

Disclosed herein are novel compounds for degrading Tau protein aggregates, pharmaceutical acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof. Also disclosed herein are uses of the compounds, pharmaceutical acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof in the manufacture of a medicament for treating a tauopathy, as well as method for aiding in the treatment of a tauopathy or treating a tauopathy in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International PatentApplication No. PCT/US2020/060459, filed Nov. 13, 2020, which claimspriority to U.S. Provisional Application No. 62/935,017, filed Nov. 13,2019, the contents of each of which are incorporated herein by referencein their entirety.

BACKGROUND

Neurodegenerative diseases affect an estimated 50 million Americans eachyear, exacting an incalculable personal toll and an annual economic costof hundreds of billions of dollars in medical expenses and lostproductivity. Tauopathies are a class of neurodegenerative diseasesassociated with pathological aggregation of Tau protein(microtubule-associated protein tau, MAPT) in the human brain, andinclude Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS),Huntington's disease (HD), Parkinson's disease (PD), Pick's Disease(PiD), and Progressive Supranuclear Palsy (PSP). In tauopathy,aggregation of Tau spreads through the brain in a prion-like manner,such as seen in AD brain (H. Braak et al., Neurobiol Aging (1995),16(3):271-78; H. Braak et al., Acta Neuropathol (2006) 112(4):389-404),where Tau pathology manifests in a consistent spatiotemporal pattern.Tau propagation seeds, consisting mainly of short fibrils, have beenfound to be significantly enriched in the synaptic fractions of brainregions lacking extensive cellular Tau pathology, indicating that Tauseeds are able to spread through the human brain alongsynaptically-connected neuronal networks.

Despite many therapeutic approaches aimed at removing aggregated Tauspecies that have been or are currently being investigated, at presentthere are no effective treatments for halting, preventing, or reversingthe progression of such neurodegenerative diseases. Therefore, there isa need for new strategies aimed at removing or reducing Tau aggregationthat may possess therapeutic potential in the treatment of patients withtauopathies.

SUMMARY

The present disclosure relates to novel bispecific conjugate compoundsthat bind to Tau aggregates, and recruit a ubiquitin E3 ligase to markthe aggregates for proteomic degradation and clearance. These compoundsbind specifically to Tau aggregates, and discriminate between Tauaggregates and monomeric (normal) Tau. These results suggest thesuitability of compounds for use in the clinic, where they have thepotential for promoting the clearance of pathogenic Tau with minimaleffects on normal/physiological Tau species in the brains of humantauopathy patients.

The present disclosure provides compositions and methods for thetreatment of a group of disorders and abnormalities associated with Tauaggregates. Methods of the invention include the administration of abispecific conjugate described herein or a pharmaceutical composition toa subject comprising a therapeutically effective amount of a compound ofthe invention effective to treat, alleviate or prevent a disorder orabnormality associated with Tau aggregates. In certain embodiments, atherapeutically effective amount of a compound described herein iseffective for halting, preventing, or reversing the progression ofneurodegenerative diseases.

In some embodiments, pharmaceutical compositions of compounds for thetreatment of Tau-associated neurodegenerative diseases are provided.Provided compositions comprise an effective amount of a compound asdescribed herein, and a pharmaceutically acceptable excipient.

One aspect of the disclosure is a compound of Formula A,

EBM-L-TBM   (Formula A)

wherein

EBM is a ubiquitin E3 ligase binding moiety;

L is a linker covalently attached to EBM and TBM; and

TBM is a tau protein binding moiety of the formula:

or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, atautomer, a racemate, a solvate, a metabolic precursor, a prodrugthereof, wherein

is covalently linked to L; and

(i)

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; or

(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N.

Another aspect of the disclosure is a compound of any one of the Formula(I)-(VI):

or pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,or prodrugs thereof, wherein L₁, L₂, L₃, X, Y, J, Q, K, T, U, V, Z, Y₁,R′, R″, R′″, R^(2′), R^(3′), n, m, k and m6 are as defined herein.

Another aspect of the disclosure is a composition comprising a compoundof the disclosure, and a pharmaceutically acceptable excipient.

Another aspect of the disclosure is a method for aiding in the treatmentof a tauopathy in a subject, the method comprising administering aneffective amount of a compound of the disclosure, or the composition thedisclosure, wherein the compound or the composition treats the subjector aids in the treatment of the subject.

Another aspect of the disclosure is the use of a compound of thedisclosure in the treatment of a tauopathy or a tau-associated diseaseor disorder.

Another aspect of the disclosure is the use of a compound of thedisclosure for the manufacture of a medicament for the treatment of atauopathy or a tau-associated disease or disorder.

Another aspect of the disclosure is a kit, comprising a compound of thedisclosure, or the composition of the disclosure, and printedinstructions for the use thereof

Another aspect of the disclosure is a method for synthesizing thecompounds of the disclosure.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative embodiments andfeatures described herein, further aspects, embodiments, objects andfeatures of the disclosure will become fully apparent from the drawingsand the detailed description and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE shows the degradation of Tau aggregates measured by APNmAb005ELISA assay. Upon treatment of 1 μM compound 162842, Optical Density(O.D.) 450 value decreases 20% compared to vehicle, reflecting thereduction of Tau aggregates.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides compounds that specifically bind toaggregated forms of Tau protein, and also bind to a ubiquitin E3 ligase.E3 ligases are intracellular enzymes that transfer activated ubiquitinto a specific site of a targeted protein.

Ubiquitin is a highly conserved small protein (8 kDa, 76 amino acids),which is ubiquitously expressed intracellularly. After expression,ubiquitin is activated by a ubiquitin-activating enzyme (“E1”), thentransferred to a ubiquitin-conjugating enzyme (“E2”). An E3 ligasetransfers the ubiquitin from the E2 enzyme to a target substrate. Thereare estimated to be more than 600 different E3 ligases, which recognizea variety of different protein substrates. Once ubiquitinated, thesubstrate is transferred to a proteasome, which degrades the proteininto oligopeptides, eventually degrading these to single amino acids.The ubiquitin-proteasome system serves to regulate the concentration ofsome proteins, and to degrade and recycle damaged or misfolded proteins.

The present disclosure provides compositions and methods for thetreatment of a group of disorders and abnormalities associated with Tauaggregates. Methods of the invention include the administration of acompound described herein or a pharmaceutical composition to a subjectcomprising a therapeutically effective amount of a compound of theinvention effective to treat, alleviate or prevent a disorder orabnormality associated with Tau aggregates. In certain embodiments, atherapeutically effective amount of a compound described herein iseffective for halting, preventing, or reversing the progression ofneurodegenerative diseases.

One aspect of the disclosure is a compound of Formula A,

EBM-L-TBM   (Formula A)

wherein

EBM is a ubiquitin E3 ligase binding moiety;

L is a linker covalently attached to EBM and TBM; and

TBM is a tau protein binding moiety of the formula:

or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, atautomer, a racemate, a solvate, a metabolic precursor, a prodrugthereof,

-   wherein

is covalently linked to L; and

(i)

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; or

(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N.

In some embodiments, the substituted or unsubstituted bicyclic fusedaromatic ring is a substituted or unsubstituted bicyclic 5-6 system.Non-limiting examples include

In some embodiments, TBM is of Formula B or Formula C

wherein

Z is C or N; U is O, S or CH; V is N or NH;

K is CH or N; Q is CH or N; where K and Q are not N at the same time;

each occurrence of R′″ is independently selected from the groupconsisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy andhalogen; k is 0, 1, 2 or 3;

each occurrence of R′ is independently selected from the groupconsisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4;

each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl and C₃₋₆heterocycloalkyl; n is 0, 1 or 2;

J is CR⁶ or N; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J, Xand Y is N, but J and Y are not N at the same time, X and Y are not N atthe same time;

R⁶ is independently selected from the group consisting of H, NH₂, C₁₋₆alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo; and

in Formula B, V is N, where Z and U are not heteroatoms at the sametime; and

in Formula C, V is N or NH; T is CH or N; where up to two of U, Z, V andT contain heteroatoms.

In some embodiments, EBM is

wherein

R^(3′) is H or C₁₋₆ alkyl;

each occurrence of R^(2′) is independently selected from the groupconsisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and NH₂;

m6 is 0, 1, 2, 3 or 4; and

Y₁ is CH₂ or

In some embodiments, the compound is of any one of the Formula (I)-(VI):

wherein, in Formula I, R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, where Z and Uare not heteroatoms at the same time; K is CH or N; Q is CH or N; whereK and Q are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ or N; X is CR⁶ or N; Yis CR⁶ or N; where at least one of J, X and Y is N, but J and Y are notN at the same time, X and Y are not N at the same time; R⁶ isindependently selected from the group consisting of H, NH₂, C₁₋₆ alkyland C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionallysubstituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo;

in Formula II, each occurrence of R^(2′) is independently selected fromthe group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaminoand NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₂ is a substituted or unsubstituted C₁₋₅₀ hydrocarbonchain; Z is C or N; U is O, S or CH; V is N, where Z and U are notheteroatoms at the same time; K is CH or N; Q is CH or N; where K and Qare not N at the same time; each occurrence of R′″ is independentlyselected from the group consisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; each occurrenceof R′ is independently selected from the group consisting of H, halogen,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1, 2, 3 or 4;each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl and C₃₋₆ heterocycloalkyl; n is 0, 1 or2; J is CR⁶ or N; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J,X and Y is N, but J and Y are not N at the same time, X and Y are not Nat the same time; R⁶ is independently selected from the group consistingof H, NH₂, C₁₋₆ alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆alkoxy is optionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆cycloalkyl and/or halo;

in Formula III, L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, where Z and Uare not heteroatoms at the same time; K is CH or N; Q is CH or N; whereK and Q are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ or N; X is CR⁶ or N; Yis CR⁶ or N; where at least one of J, X and Y is N, but J and Y are notN at the same time, X and Y are not N at the same time; R⁶ isindependently selected from the group consisting of H, NH₂, C₁₋₆ alkyland C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionallysubstituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo;

in Formula IV, R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CHor N; where up to two of U, Z, V and T contain heteroatoms; K is CH orN; Q is CH or N; where K and Q are not N at the same time; eachoccurrence of R′″ is independently selected from the group consisting ofH, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is0, 1, 2 or 3; each occurrence of R′ is independently selected from thegroup consisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4; each occurrence of R″ is independentlyselected from the group consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino, and C₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ orN; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J, X and Y is N,but J and Y are not N at the same time, X and Y are not N at the sametime; R⁶ is independently selected from the group consisting of H, NH₂,C₁₋₆ alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo; in Formula V, each occurrence of R²′ is independently selectedfrom the group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylamino and NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₂ is a substituted or unsubstituted C₁₋₅₀ hydrocarbonchain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N; whereup to two of U, Z, V and T contain heteroatoms; K is CH or N; Q is CH orN; where K and Q are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ or N; X is CR⁶ or N; Yis CR⁶ or N; where at least one of J, X and Y is N, but J and Y are notN at the same time, X and Y are not N at the same time; R⁶ isindependently selected from the group consisting of H, NH₂, C₁₋₆ alkyland C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionallysubstituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo; inFormula VI, L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; V is N; T is CH or N;where up to two of U, Z, V and T contain heteroatoms; K is CH or N; Q isCH or N; where K and Q are not N at the same time; each occurrence ofR′″ is independently selected from the group consisting of H, OH, NH₂,C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3;each occurrence of R′ is independently selected from the groupconsisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4; each occurrence of R″ is independentlyselected from the group consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆cycloalkylamino and C₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ orN; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J, X and Y is N,but J and Y are not N at the same time, X and Y are not N at the sametime; R⁶ is independently selected from the group consisting of H, NH₂,C₁₋₆ alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo. Optionally, one or more chain atoms of the substituted orunsubstituted C₁₋₅₀ hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1)—, —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl (e.g.,substituted or unsubstituted methyl or ethyl), or a nitrogen protectinggroup (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzylcarbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl,triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).

In certain embodiments, the compound is of the structure of Formula I.

In certain embodiments, the compound is of the structure of Formula II.

In certain embodiments, the compound is of the structure of Formula III.

In certain embodiments, the compound is of the structure of Formula IV.

In certain embodiments, the compound is of the structure of Formula V.

In certain embodiments, the compound is of the structure of Formula VI.

In certain embodiments, the moiety

in Formula (I), (II) and (III) is

In certain embodiments, the moiety

in Formula (IV), (V) and (VI) is

In certain embodiments, the moiety

in Formulae (I)-(VI) is

In certain embodiments, the moiety

in Formula (I) and (IV) is

In certain embodiments, the moiety

in Formula (II) and (V) is

In one embodiment of the disclosure, L1 is a bond.

In one embodiment of the disclosure, L1 is —C(═O)—, —NH—, —O—, or —S—.

In one embodiment of the disclosure, L₃ is a bond.

In one embodiment of the disclosure, L₃ is —NH—, —O—, or —S—.

In one embodiment of the disclosure, L2 is a substituted orunsubstituted C₁₋₃₀ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1), —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group.

In certain embodiments, L₂ is an unsubstituted C₁₋₃₀ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(a1), —S— or a cyclicmoiety, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group.

In certain embodiments, L2 is a substituted or unsubstituted C₁₋₂₄hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1), —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group.

In certain embodiments, L2 is an unsubstituted C₁₋₂₄ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(a1), —S— or a cyclicmoiety, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group.

In certain embodiments, L2 is a substituted or unsubstituted C₁₋₂₀hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1), —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group.

In certain embodiments, L2 is an unsubstituted C₁₋₂₀ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with ——C(═O)—, —O—, —NR^(a1), —S— or a cyclicmoiety, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group.

In certain embodiments, at least one chain atom of the hydrocarbon chainof L2 is independently replaced with —O—.

In certain embodiments, the chain of L2 comprises up to 50 consecutivecovalently bonded atoms in length, excluding hydrogen atoms andsubstituents.

In certain embodiments, L2 comprises up to, for example 46, 45, 40, 35,32, 30, 25, 23, 20, 15, 14, 12, 11, 10, 9, 8, 7, 6, 5, 3 consecutivecovalently bonded atoms in length, excluding hydrogen atoms andsubstituents.

In certain embodiments, any of the atoms in L2 can be substituted. Incertain embodiments, none of the atoms in the linker L2 are substituted.In certain embodiments, none of the carbon atoms in the linker aresubstituted.

In certain embodiments, L2 is a linker that contains an asymmetriccarbon/stereocenter, i.e., an sp3 hybridized carbon atom bearing 4different groups attached thereto. In certain embodiments, the compoundcomprising such an L2 group is enantiomerically enriched orsubstantially enantiomerically enriched. In certain embodiments, thecompound comprising such an L2 group is enantiomerically pure. Incertain embodiments, the compound comprising such an L2 group isracemic.

In certain embodiments, L2 comprises substituted or unsubstitutedcarbocyclylene, substituted or unsubstituted heterocyclylene,substituted or unsubstituted arylene, substituted or unsubstitutedheteroarylene, or substituted or unsubstituted heteroalkylene, orcombinations thereof. In certain embodiments, L2 is substituted orunsubstituted carbocyclylene, substituted or unsubstitutedheterocyclylene, substituted or unsubstituted arylene, substituted orunsubstituted heteroarylene, or substituted or unsubstitutedheteroalkylene. In certain embodiments, L2 is a linker selected from thegroup consisting of substituted and unsubstituted alkylene, substitutedand unsubstituted alkenylene, substituted and unsubstituted alkynylene,substituted and unsubstituted heteroalkylene, substituted andunsubstituted heteroalkenylene, substituted and unsubstitutedheteroalkynylene, substituted and unsubstituted heterocyclylene,substituted and unsubstituted carbocyclylene, substituted andunsubstituted arylene, substituted and unsubstituted heteroarylene, andcombinations thereof

Reference to L2 being a combination of at least two instances of thedivalent moieties described herein refers to a linker consisting of atleast one instance of a first divalent moiety and at least one instanceof a second divalent moiety, wherein the first and second divalentmoieties are the same or different and are within the scope of thedivalent moieties described herein, and the instances of the first andsecond divalent moieties are consecutive covalently attached to eachother. For example, when L2 is a combination of alkylene andheteroalkylene linkers, -alkylene-heteroalkylene-,-alkylene-(heteroalkylene)₂-, and-heteroalkylene-alkylene-heteroalkylene- are all within the scope of L2,wherein each instance of alkylene in any one of the linkers may be thesame or different, and each instance of heteroalkylene in any one of thelinkers may be the same or different.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted alkylene, e.g., substituted orunsubstituted C₁₋₆ alkylene, substituted or unsubstituted C₁₋₂ alkylene,substituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₃₋₄ alkylene, substituted or unsubstituted C₄₋₅ alkylene, substitutedor unsubstituted C₅₋₆ alkylene, substituted or unsubstituted C₃₋₆alkylene, or substituted or unsubstituted C₄₋₆ alkylene. Exemplaryalkylene groups include unsubstituted alkylene groups such as methylene(—CH₂—), ethylene (—(CH₂)₂—), n-propylene (—(CH₂)₃—), n-butylene(—(CH₂)₄—), n-pentylene (—(CH₂)₅—), and n-hexylene (—(CH₂)₆—).

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted alkenylene, e.g., substituted orunsubstituted C₂₋₆ alkenylene, substituted or unsubstituted C₁₋₃alkenylene, substituted or unsubstituted C₃₋₄ alkenylene, substituted orunsubstituted C₄₋₅ alkenylene or substituted or unsubstituted C₅₋₆alkenylene.

In certain embodiments, L₂ comprises at least one instance ofsubstituted or unsubstituted alkynylene, e.g., substituted orunsubstituted C₂₋₆ alkynylene, substituted or unsubstituted C₂₋₃alkynylene, substituted or unsubstituted C₃₋₄ alkynylene, substituted orunsubstituted C₄₋₅ alkynylene or substituted or unsubstituted C₅₋₆alkynylene.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted heteroalkylene, e.g., substituted orunsubstituted heteroC₁₋₆alkylene, substituted or unsubstitutedheteroC₁₋₂alkylene, substituted or unsubstituted heteroC₂₋₃alkylene,substituted or unsubstituted heteroC₃₋₄alkylene, substituted orunsubstituted heteroC₄₋₅alkylene or substituted or unsubstitutedheteroC₅₋₆alkylene. Exemplary heteroalkylene groups includeunsubstituted heteroalkylene groups, such as (—CH₂)₂—O(CH₂)₂—, OCH₂—,—CH₂O—, —O(CH₂)₂—, —(CH₂)₂O—, —O(CH₂)₃—, —(CH₂)₃O—, —O(CH₂)₄—,—(CH₂)₄O—, —O(CH₂)₅—, —(CH₂)₅O—, —O(CH₂)₆—, and —O(CH₂)₆O—, and amidegroups (e.g., —NH—C(═O)— and —C(═O)NH—).

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted heteroalkenylene, e.g., substituted orunsubstituted heteroC₂₋₆alkenylene, substituted or unsubstitutedheteroC₁₋₃alkenylene, substituted or unsubstituted heteroC₃₋₄alkenylene,substituted or unsubstituted heteroC₄₋₅alkenylene, or substituted orunsubstituted heteroC₅₋₆alkenylene.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted heteroalkynylene, e.g., substituted orunsubstituted heteroC₂₋₆alkynylene, substituted or unsubstitutedheteroC₂₋₃alkynylene, substituted or unsubstituted heteroC₃₋₄alkynylene, substituted or unsubstituted heteroC₄₋₅alkynylene, orsubstituted or unsubstituted heteroC5-6alkynylene.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted carbocyclylene, e.g., substituted orunsubstituted C₃₋₆carbocyclylene, substituted or unsubstitutedC₃₋₄carbocyclylene, substituted or unsubstituted C4-5carbocyclylene, orsubstituted or unsubstituted C₅₋₆ carbocyclylene.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted heterocyclylene, e.g., substituted orunsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted3-4 membered heterocyclylene, substituted or unsubstituted 4-5 memberedheterocyclylene, or substituted or unsubstituted 5-6 memberedheterocyclylene. In certain embodiments, at least one chain atom of thehydrocarbon chain of L2 is independently replaced with a 5-8 memberedheterocyclyl group with 1-4 ring heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one chain atom of the hydrocarbon chain of L2 is independentlyreplaced with a 6-membered heterocyclyl group with 1-3 ring heteroatomsselected from the group consisting of nitrogen and oxygen. In certainembodiments, at least one chain atom of the hydrocarbon chain of L2 isindependently replaced with piperidine, piperazine or morpholine.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted arylene, e.g., substituted or unsubstitutedphenylene. In certain embodiments, at least one chain atom of thehydrocarbon chain of L2 is independently replaced with an optionallysubstituted phenyl group.

In certain embodiments, L2 comprises at least one instance ofsubstituted or unsubstituted heteroarylene, e.g., substituted orunsubstituted 5- to 6-membered heteroarylene.

In certain embodiments, L2 is an unsubstituted hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —NR^(a1)—, and each instance of R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group, or optionally two instances of R^(a1) aretaken together with their intervening atoms to form a substituted orunsubstituted heterocyclic or substituted or unsubstituted heteroarylring. In certain embodiments, at least one instance of R^(a1) ishydrogen. In certain embodiments, at least one instance of R^(a1) issubstituted or unsubstituted C₁₋₆ alkyl (e.g., substituted orunsubstituted methyl or ethyl). In certain embodiments, at least oneinstance of R^(a1) is a nitrogen protecting group (e.g., benzyl (Bn),t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz),9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl,acetyl or p-toluenesulfonamide (Ts)).

In certain embodiments, L2 is an optionally substituted C₁₋₄₅hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1), —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group. In certain embodiments, L2 is an unsubstituted C₁₋₄₅hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1), —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group. In certain embodiments, L2 is an optionallysubstituted C₁₋₂₄ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1), —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group. In certain embodiments, L2 is anunsubstituted C₁₋₂₄ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1)—, —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group. In certain embodiments, L2 is an optionallysubstituted C₁₋₂₀ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1), —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group. In certain embodiments, L2 is anunsubstituted C₁₋₂₀ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(a1), —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group. In certain embodiments, L2 is an optionallysubstituted C₁₋₃₀ hydrocarbon chain, wherein one or more chain atoms ofthe hydrocarbon chain are independently replaced with —O— or —NR^(a1)—.In certain embodiments, L2 is an unsubstituted C₁₋₃₀ hydrocarbon chain,wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —O— or —NR^(a1)—. In certain embodiments, L2is an unsubstituted C₁₋₃₀ hydrocarbon chain, wherein at least one chainatom of the hydrocarbon chain is independently replaced with —O—. Incertain embodiments, L2 is an unsubstituted C₁₋₂₆ hydrocarbon chain,wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O— or —NR^(a1)—. In certainembodiments, L2 is an unsubstituted C₁₋₂₀ hydrocarbon chain, wherein oneor more chain atoms of the hydrocarbon chain are independently replacedwith —O—. In certain embodiments, L2 is an unsubstituted C₅₋₂₆hydrocarbon chain, wherein one or more chain atoms of the hydrocarbonchain are independently replaced with —C(═O)—, —O— or —NR^(a1)—. Incertain embodiments, L2 is an unsubstituted C₅₋₂₆ hydrocarbon chain,wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —O—. In certain embodiments, L2 is anunsubstituted C₅₋₂₀ hydrocarbon chain, wherein one or more chain atomsof the hydrocarbon chain are independently replaced with —C(═O)—, —O— or—NR^(a1)—In certain embodiments, L2 is an unsubstituted C₅₋₂₀hydrocarbon chain, wherein one or more chain atoms of the hydrocarbonchain are independently replaced with —O—, or —NR^(a1)—. In certainembodiments, L2 is an unsubstituted C₅₋₁₅ hydrocarbon chain, wherein oneor more chain atoms of the hydrocarbon chain are independently replacedwith —C(═O)—, —O— or —NR^(a1)—. In certain embodiments, L2 is anunsubstituted C₁₅₋₂₀ hydrocarbon chain, wherein one or more chain atomsof the hydrocarbon chain are independently replaced with —C(═O)—, —O— or—NR^(a1)—. In certain embodiments, L2 is an unsubstitutedC₂₀₋₂₅hydrocarbon chain, wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O— or—NR^(a1)—. In certain embodiments, L2 is a substituted or unsubstitutedC₁₋₄₅ hydrocarbon chain. In certain embodiments, L2 is a substituted orunsubstituted C₅₋₄₀ hydrocarbon chain. In certain embodiments, one ormore chain atoms of the hydrocarbon chain of L2 are independentlyreplaced with —C(═O)—, —O—, —S—, —NR^(a1)—, —N═ or ═N—. In certainembodiments, one or more chain atoms of the hydrocarbon chain of L2 areindependently replaced with —C(═O)—, —O— or —NR^(a1)—, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group. In certain embodiments, L2 is anunsubstituted C₁₋₂₆ hydrocarbon chain, wherein at least one chain atomof the hydrocarbon chain is independently replaced with —O—. The cyclicmoiety herein refers to a cycloalkylene or a heterocycloalkylene, suchas

In certain embodiments, L2 is an all-carbon, substituted orunsubstituted C₁₋₄₅ hydrocarbon chain. In certain embodiments, L2 is anall-carbon, substituted or unsubstituted C₁₋₃₀ hydrocarbon chain. Incertain embodiments, L2 is an all-carbon, substituted or unsubstitutedC₁₋₂₆ hydrocarbon chain. In certain embodiments, L2 is an all-carbon,substituted or unsubstituted C₁₋₂₄ hydrocarbon chain. In certainembodiments, L2 is an all-carbon, substituted or unsubstituted C₁₋₂₀hydrocarbon chain. In certain embodiments, L2 is an all-carbon,substituted or unsubstituted C₁₋₂₀ hydrocarbon chain.

In certain embodiments, L2 is

wherein g is 1, 2, 3, 4, 5, or 6. In certain embodiments, g is 1. Incertain embodiments, g is 2. In certain embodiments, g is 3. In certainembodiments, g is 4. In certain embodiments, g is 5. In certainembodiments, g is 6.

In certain embodiments, L2 comprises at least one instance selected fromthe group consisting of substituted or unsubstituted methylene,ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,—(CH₂)₂—O(CH₂)₂—, —OCH₂—, —CH₂O—, —O(CH₂)₂—, —(CH₂)₂O—, —O(CH₂)₃—,—(CH₂)₃O—, —O(CH₂)₄—, —(CH₂)₄O—, —O(CH₂)₅—, —(CH₂)₅O—, —O(CH₂)₆—,—O(CH₂)₆O—, —C(═O)O—, —O—C(═O)—, —NH—C(═O)— and —C(═O)NH—.

In certain embodiments, L₂ comprises at least one instance selected fromthe group consisting of substituted or unsubstituted methylene,ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,—(CH₂)₂—O(CH₂)₂—, —OCH₂—, —CH₂O—, —O(CH₂)₂—, —(CH₂)₂O—, —O(CH₂)₃—,—(CH₂)₃O—, —O(CH₂)₄—, —(CH₂)₄O—, —O(CH₂)₅—, —(CH₂)₅O—, —O(CH₂)₆—,—O(CH₂)₆O—, —NH—C(═O)— and —C(═O)NH—.

In certain embodiments, L2 includes the moiety —NHC(═O—.

In certain embodiments, L2 includes the moiety —NH—.

Examples of L2 of the disclosure include, but are not limited to:

wherein each g is independently 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5,or 6, and his 1, 2, 3, 4, 5, or 6.

In certain embodiments, L2 is of the formula:

In certain embodiments, L2 is of the formula:

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4 or 5; h is 0, 1, 2, 3, 4 or 5; and f is 1, 2, 3,4, 5, 6, 7 or 8.

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or8.

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or8.

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or8.

In certain embodiments, L2 is of the formula:

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, the compound of the disclosure is of any one ofthe structure as follows,

wherein, in Formula I-1, R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; where Z and U are notheteroatoms at the same time; Q is CH or N; K is CH or N; where Q and Kare not N at the same time; each occurrence of R′″ is independentlyselected from the group consisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; each occurrenceof R′ is independently selected from the group consisting of H, halogen,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1, 2, 3 or 4;each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino and C₃₋₆heterocycloalkyl; n is 0, 1 or 2; in Formula II-1, each occurrence ofR^(2′) is independently selected from the group consisting of H, OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and NH₂; m6 is 0, 1, 2, 3 or 4;Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; where Z and U are notheteroatoms at the same time; Q is CH or N; K is CH or N; where Q and Kare not N at the same time; each occurrence of R′″ is independentlyselected from the group consisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; each occurrenceof R′ is independently selected from the group consisting of H, halogen,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1, 2, 3 or 4;each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino and C₃₋₆heterocycloalkyl; n is 0, 1 or 2;

in Formula III-1, L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; where Z and U are notheteroatoms at the same time; Q is CH or N; K is CH or N; where Q and Kare not N at the same time; each occurrence of R′″ is independentlyselected from the group consisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; each occurrenceof R′ is independently selected from the group consisting of H, halogen,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1, 2, 3 or 4;each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino and C₃₋₆heterocycloalkyl; n is 0, 1 or 2;

in Formula IV-1, R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; whereonly one of U, Z and T is heteroatom; Q is CH or N; K is CH or N; whereQ and K are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; X is CR⁶ or N; Y is CR⁶ or N;where one of X and Y is N, while the other is CR⁶; R⁶ is independentlyselected from the group consisting of H, NH₂, C₁₋₆ alkyl and C₁₋₆alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionally substitutedby 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo;

in Formula V-1, each occurrence of R^(2′) is independently selected fromthe group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaminoand NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; whereonly one of U, Z and T is heteroatom; Q is CH or N; K is CH or N; whereQ and K are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; X is CR⁶ or N; Y is CR⁶ or N;where one of X and Y is N, while the other is CR⁶; R⁶ is independentlyselected from the group consisting of H, NH₂, C₁₋₆ alkyl and C₁₋₆alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionally substitutedby 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo;

in Formula VI-1, L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₃ is a bond, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; whereonly one of U, Z and T is heteroatom; Q is CH or N; K is CH or N; whereQ and K are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylamino andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; X is CR⁶ or N; Y is CR⁶ or N;where one of X and Y is N, while the other is CR⁶; R⁶ is independentlyselected from the group consisting of H, NH₂, C₁₋₆ alkyl and C₁₋₆alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionally substitutedby 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo.

In certain embodiments, the compound of Formula I-1 is of the followingFormula 1, 5, 6, 8, 10 or 13,

wherein

each A is independently O, NH,

m2 is 1, 2, 3, 4, 5, 6, or 7;

m3 is 1, 2, 3, 4, 5, or 6;

m4 is 0, 1, 2, or 3;

m5 is 0, 1, 2, or 3; and

R″ is O, NH,

An embodiment of the disclosure is the compound of Formula 1, wherein R′is H, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferably H, CF₃, CCl₃, methoxy orethoxy, more preferably H, CF₃ or methoxy.

An embodiment of the disclosure is the compound of Formula 1, wherein mis 0, 1, 2, 3 or 4, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 1, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino and C₃₋₅ heterocycloalkyl, preferably H, F, Cl, NH₂,methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino,cyclopropyl, cyclobutyl or cyclopentyl, more preferably H, F,dimethylamino or cyclopropyl.

An embodiment of the disclosure is the compound of Formula 1, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 1, whereinR′″ is H, OH or halogen, preferably H, OH, F or Cl, more preferably H.

An embodiment of the disclosure is the compound of Formula 1, wherein kis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 1, whereinR^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 1, whereinR^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 1, wherein Ais O, NH,

preferably O or

An embodiment of the disclosure is the compound of Formula 1, wherein m2is 2, 3, 4 or 6, preferably 2 or 6.

An embodiment of the disclosure is the compound of Formula 1, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl, more preferably H.

An embodiment of the disclosure is the compound of Formula 1 having thestructure as shown in Formula 1-1,

In Formula 1-1, R^(3′) is H or C₁₋₃ alkyl; Y₁ is CH₂ or

A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 and 7; R^(1′) is O, NH,

U is O, S or CH; Z is C or N; where U and Z are not heteroatoms at thesame time; R′ is H, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; R″ is H, F, Cl, OH,NH₂, C₁₋₃ alkoxy, methylamino, dimethylamino, diethylamino orcyclopropylamino; n is 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 1-1, whereinm2 is 2, 3, 4 or 6, preferably 2 or 6.

An embodiment of the disclosure is the compound of Formula 1-1, whereinR^(3′) is H or methyl.

An embodiment of the disclosure is the compound of Formula 1-1, whereinA is O or

An embodiment of the disclosure is the compound of Formula 1-1, whereinR^(1′) is O, NH or

An embodiment of the disclosure is the compound of Formula 1-1, whereinR^(1″) is O, NH,

An embodiment of the disclosure is the compound of Formula 1-1, whereinZ is N, U is CH.

An embodiment of the disclosure is the compound of Formula 1-1, whereinZ is C, U is S or O.

An embodiment of the disclosure is the compound of Formula 1-1, whereinR″ is H, F, Cl, OH, NH₂, methoxy, methylamino, dimethylamino,diethylamino, cyclopropyl or cyclopropylamino, preferably H, F,methylamino, dimethylamino or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 1-1, whereinR′ is H, C₁₋₃ fluoroalkyl, methoxy or ethoxy, preferably R′ is H,methoxy or CF₃.

An embodiment of the disclosure is the compound of Formula 5, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 5, wherein Ais O, NH or

preferably O. An embodiment of the disclosure is the compound of Formula5, wherein each A is independently O, NH,

An embodiment of the disclosure is the compound of Formula 5, wherein m4is 0, 1, 2, or 3, preferably 0 or 3.

An embodiment of the disclosure is the compound of Formula 5, wherein m5is 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 5, wherein m3is 1, 2, 3, 4, 5 or 6, preferably 3 or 5.

An embodiment of the disclosure is the compound of Formula 5, whereinR^(1′) is O, NH or

An embodiment of the disclosure is the compound of Formula 5, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, methyl,methoxy or F, more preferably H.

An embodiment of the disclosure is the compound of Formula 5, wherein kis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 5, wherein Zis C, U is O or S.

An embodiment of the disclosure is the compound of Formula 5, wherein Zis N, U is CH.

An embodiment of the disclosure is the compound of Formula 5, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 5, wherein mis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 5, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, cyclopropyl or dimethylamino, more preferably H, F, CF₃,cyclopropyl, cyclopropylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 5, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 5 having thestructure as shown in Formula 5-1,

In Formula 5-1, R^(3′) is H or C₁₋₃ alkyl; Y₁ is CH₂ or

A is O, NH,

m5 is 0 or 1; m4 is 0, 1, 2, 3 or 4; m3 is 1, 2, 3, 4, 5 or 6; is O, NH,

Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at thesame time; R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; R′ is H,halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; R″ is H, halo,OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylamino and C₃₋₅ heterocycloalkyl; n is 0, 1 or2.

An embodiment of the disclosure is the compound of Formula 5-1, whereinA is O.

An embodiment of the disclosure is the compound of Formula 5-1, whereinm5 is 0 or 1.

An embodiment of the disclosure is the compound of Formula 5-1, whereinm4 is 0 or 3.

An embodiment of the disclosure is the compound of Formula 5-1, whereinm3 is 3, 5.

An embodiment of the disclosure is the compound of Formula 5-1, whereinR^(1′) is O, NH or

An embodiment of the disclosure is the compound of Formula 5-1, whereinZ is C, U is O or S.

An embodiment of the disclosure is the compound of Formula 5-1, whereinZ is N, U is CH.

An embodiment of the disclosure is the compound of Formula 5-1, whereinR′ is H, halogen, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl or C₁₋₃ alkoxy,preferably H, methyl, CF₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 5-1, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, CF₃, amino, methylamino,dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F,CF₃, dimethylamino, cyclopropylamino or cyclopropyl.

An embodiment of the disclosure is the compound of Formula 6, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 6, wherein Ais O, NH or

preferably O or NH.

An embodiment of the disclosure is the compound of Formula 6, wherein m2is 1, 2, 3, 4, 5, 6 or 7, preferably 2 or 6.

An embodiment of the disclosure is the compound of Formula 6, whereinR^(1′) is O, NH or

preferably O or NH.

An embodiment of the disclosure is the compound of Formula 6, wherein Zis C or N, and U is O, S or CH, where Z and U are not heteroatoms at thesame time; preferably Z is C and U is S.

An embodiment of the disclosure is the compound of Formula 6, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, methyl,methoxy or F, more preferably H.

An embodiment of the disclosure is the compound of Formula 6, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 6, wherein mis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 6, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, cyclopropyl, cyclopropylamino or dimethylamino, morepreferably H, F, CF₃, dimethylamino, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 6, wherein nis 0 or 1.

An embodiment of the disclosure is the compound of Formula 6 having thestructure as shown in Formula 6-1,

In Formula 6-1, R^(3′) is H or C₁₋₃ alkyl; Y₁ is CH₂ or

A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 or 7; R^(1′) is O, NH,

R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; k is 0, 1, 2 or 3; Zis C or N; U is O, S or CH; where Z and U are not heteroatoms at thesame time; R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃alkoxy; m is 0, 1, 2 or 3; R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₃₋₅ heterocycloalkyl; n is 0, 1 or 2.

In some embodiments of Formula 6-1, R^(3′) is H or C₁₋₃ alkyl; Y₁ is CH₂or

A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 or 7; R^(1′) is O, NH,

R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; k is 0, 1, 2 or 3; Zis C or N; U is O, S or CH; where Z and U are not heteroatoms at thesame time; R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃alkoxy; m is 0, 1, 2 or 3; R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C3-scycloalkylamino or C₃₋₅ heterocycloalkyl; n is 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 6-1, whereinR^(3′) is H or methyl.

An embodiment of the disclosure is the compound of Formula 6-1, whereinA is O or NH.

An embodiment of the disclosure is the compound of Formula 6-1, whereinm2 is 2 or 6.

An embodiment of the disclosure is the compound of Formula 6-1, whereinR^(1′) is O, or NH.

An embodiment of the disclosure is the compound of Formula 6-1, whereinR′ is H or CF₃.

An embodiment of the disclosure is the compound of Formula 6-1, whereinm is 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 6-1, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, CF₃, methoxy, methyl, dimethylamino,cyclopropyl, cyclopropylamino or methylamino, more preferably H, CF₃, F,dimethylamino, cyclopropyl or cyclopropylamino, most preferably H,dimethylamino, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 6-1, whereinn is 0 or 1.

An embodiment of the disclosure is the compound of Formula 6-1, whereinR″ substitutes at the adjacent position to the N atom.

An embodiment of the disclosure is the compound of Formula 8, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 8, wherein Y₁is CH₂ or

preferably CH₂.

An embodiment of the disclosure is the compound of Formula 8, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 8, wherein m2is 1, 2, 3 or 4, preferably 2.

An embodiment of the disclosure is the compound of Formula 8, whereinR^(1′) is O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 8, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, methyl,methoxy or F, more preferably H.

An embodiment of the disclosure is the compound of Formula 8, wherein kis 0 or 1.

An embodiment of the disclosure is the compound of Formula 8, wherein Zis C or N; U is O, S or CH; where Z and U are not heteroatoms at thesame time; preferably Z is N and U is CH; preferably Z is C and U is S.

An embodiment of the disclosure is the compound of Formula 8, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 8, wherein mis 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 8, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 8, wherein nis 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 8 having thestructure of

An embodiment of the disclosure is the compound of Formula 10, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 10, whereinY₁ is CH₂ or

preferably CH₂.

An embodiment of the disclosure is the compound of Formula 10, whereineach A is independently O, NH,

An embodiment of the disclosure is the compound of Formula 10, wherein Ais O, NH,

preferably

An embodiment of the disclosure is the compound of Formula 10, whereinm5 is 0 or 1.

An embodiment of the disclosure is the compound of Formula 10, whereinm4 is 0 or 1.

An embodiment of the disclosure is the compound of Formula 10, whereinm3 is 1, 2, 3, 4 or 5, preferably 4.

An embodiment of the disclosure is the compound of Formula 10, whereinR″ is O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 10, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, methyl,methoxy or F, more preferably H.

An embodiment of the disclosure is the compound of Formula 10, wherein kis 0 or 1.

An embodiment of the disclosure is the compound of Formula 10, wherein Zis C, U is S or O.

An embodiment of the disclosure is the compound of Formula 10, wherein Zis N, U is CH.

An embodiment of the disclosure is the compound of Formula 10, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 10, wherein mis 0 or 1.

An embodiment of the disclosure is the compound of Formula 10, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, cyclopropyl, cyclopropylamino or dimethylamino, morepreferably H, F or CF₃.

An embodiment of the disclosure is the compound of Formula 10, wherein nis 0 or 1.

An embodiment of the disclosure is the compound of Formula 13, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 13, whereinY₁ is CH₂ or

preferably CH₂.

An embodiment of the disclosure is the compound of Formula 13, wherein Ais O, NH,

preferably

An embodiment of the disclosure is the compound of Formula 13, whereinm2 is 1, 2, 3 or 4, preferably 1.

An embodiment of the disclosure is the compound of Formula 13, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 13, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, methyl,methoxy or F, more preferably H.

An embodiment of the disclosure is the compound of Formula 13, wherein kis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 13, wherein Zis C, U is S or O.

An embodiment of the disclosure is the compound of Formula 13, wherein Zis N, U is CH.

An embodiment of the disclosure is the compound of Formula 13, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 13, wherein mis 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 13, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, cyclopropyl, cyclopropylamino or dimethylamino, morepreferably H, F, CF₃, dimethylamino, cyclopropyl or cyclopropylamino,most preferably dimethylamino.

An embodiment of the disclosure is the compound of Formula 13, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the compound of Formula II-1 is of the followingFormula 3,

wherein R^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 3, whereinR²′ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylamino or NH₂,preferably H, OH or NH₂.

An embodiment of the disclosure is the compound of Formula 3, wherein m6is 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 3, whereinR^(1′) is O or NH.

An embodiment of the disclosure is the compound of Formula 3, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, halogen or C₁₋₃ fluoroalkyl, more preferably H or F.

An embodiment of the disclosure is the compound of Formula 3, wherein mis 0, 1, 2, 3 or 4, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 3, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylaminoor C₁₋₃ alkylamino, preferably H, halo, methylamino, dimethylamino,cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

An embodiment of the disclosure is the compound of Formula 3, wherein nis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 3, wherein Zis C, U is O or S.

An embodiment of the disclosure is the compound of Formula 3, wherein Zis N, U is CH.

An embodiment of the disclosure is the compound of Formula 3, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, F,methyl or methoxy, more preferably H.

An embodiment of the disclosure is the compound of Formula 3 having thestructure as shown in Formula 3-1,

In Formula 3-1, R^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino or NH₂; m6 is 0, 1, 2 or 3; Y₁ is CH₂ or

R^(1′) is O, NH,

Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at thesame time; R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₅cycloalkyl, C₃₋₅ cycloalkylamino or C₁₋₃ alkylamino; n is 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 3-1, whereinR^(2′) is H, NH₂ or OH.

An embodiment of the disclosure is the compound of Formula 3-1, whereinm6 is 0 or 1.

An embodiment of the disclosure is the compound of Formula 3-1, whereinwhen m6 is 1, R^(2′) is substituted at the following position in thephenyl:

An embodiment of the disclosure is the compound of Formula 3-1, whereinR″ is O or NH.

An embodiment of the disclosure is the compound of Formula 3-1, whereinR″ is F, dimethylamino, methylamino, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 3-1, whereinn is 0, 1, or 2.

An embodiment of the compound of Formula III-1 is of the followingFormula 15,

wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 15, whereinm2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, 4, 5 or 6, morepreferably 2 or 5.

An embodiment of the disclosure is the compound of Formula 15, whereinR^(1′) is O, NH,

preferably O or NH.

An embodiment of the disclosure is the compound of Formula 15, whereinR′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen, preferably H, F,methyl or methoxy, more preferably H.

An embodiment of the disclosure is the compound of Formula 15, wherein Zis C, U is O or S.

An embodiment of the disclosure is the compound of Formula 15, wherein Zis N, U is CH.

An embodiment of the disclosure is the compound of Formula 15, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, halogen or C₁₋₃fluoroalkyl, more preferably H, CF₃ or F.

An embodiment of the disclosure is the compound of Formula 15, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 15, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₁₋₃ alkylamino, preferably H, halo, methylamino,dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F,methylamino, cyclopropylamino or dimethylamino, most preferably H ordimethylamino.

An embodiment of the disclosure is the compound of Formula 15, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the compound of Formula IV-1 is of the followingFormula 2, 7, 9, 11, 12 or 14,

wherein

each A is independently O, NH,

m2 is 2, 3, 4, 5, or 6;

m3 is 1, 2, 3, 4, 5, or 6;

m4 is 0, 1, 2, 3, or 4;

m5 is 0, 1, 2, or 3; and

R^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 2, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 2, wherein Y₁is CH₂ or

An embodiment of the disclosure is the compound of Formula 2, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 2, wherein m2is 2, 3, 4, 5 or 6, preferably 2 or 6.

An embodiment of the disclosure is the compound of Formula 2, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 2, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 2, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 2, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF_(3.)

An embodiment of the disclosure is the compound of Formula 2, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 2, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 2, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 2, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 2, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 2, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 7, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 7, wherein Y₁is CH₂ or

An embodiment of the disclosure is the compound of Formula 7, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 7, wherein m2is 2, 3, 4, 5 or 6, preferably 2 or 3.

An embodiment of the disclosure is the compound of Formula 7, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 7, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 7, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 7, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 7, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 7, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 7, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 7, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 7, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 7, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 9, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 9, wherein Y₁is CH₂ or

An embodiment of the disclosure is the compound of Formula 9, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 9, wherein m2is 2, 3, 4, 5 or 6, preferably 2 or 3.

An embodiment of the disclosure is the compound of Formula 9, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 9, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 9, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 9, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 9, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 9, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 9, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 9, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 9, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 9, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 11, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 11, whereinY₁ is CH₂ or

An embodiment of the disclosure is the compound of Formula 11, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 11, whereinm2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

An embodiment of the disclosure is the compound of Formula 11, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 11, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 11, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 11, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 11, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 11, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 11, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 11, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 11, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 11, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 12, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 12, whereinY₁ is CH₂ or

preferably CH₂.

An embodiment of the disclosure is the compound of Formula 12, whereineach A is independently O, NH,

An embodiment of the disclosure is the compound of Formula 12, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 12, whereinm3 is 1, 2, 3, 4, 5 or 6, preferably 2 or 3.

An embodiment of the disclosure is the compound of Formula 12, whereinm4 is 0 or 1, 2 or 3, preferably 0 or 3.

An embodiment of the disclosure is the compound of Formula 12, whereinm5 is 0 or 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 12, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 12, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 12, wherein nis 0, 1 or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 12, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 12, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 12, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 12, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 12, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 12, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 12, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 14, whereinR^(3′) is H or C₁₋₃ alkyl, preferably H or methyl.

An embodiment of the disclosure is the compound of Formula 14, whereinY₂ is CH₂ or

preferably CH₂.

An embodiment of the disclosure is the compound of Formula 14, whereineach A is independently O, NH,

An embodiment of the disclosure is the compound of Formula 14, wherein Ais O, NH,

preferably O.

An embodiment of the disclosure is the compound of Formula 14, whereinm3 is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

An embodiment of the disclosure is the compound of Formula 14, whereinm4 is 0 , 1, 2, 3 or 4, preferably 0 or 3.

An embodiment of the disclosure is the compound of Formula 14, whereinm5 is 0 or 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 14, whereinR^(1′) is O, NH,

preferably

An embodiment of the disclosure is the compound of Formula 14, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl, preferably H, F, OH, NH₂, methyl, methoxy, CF₃, CCl₃,methylamino, dimethylamino, cyclopropyl or cyclopropylamino, morepreferably H, F, CF₃, cyclopropyl or cyclopropylamino.

An embodiment of the disclosure is the compound of Formula 14, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 14, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, F, CF₃, CCl₃, methyl or methoxy, more preferably H or CF₃.

An embodiment of the disclosure is the compound of Formula 14, wherein mis 0, 1, 2 or 3, preferably 0, 1 or 2.

An embodiment of the disclosure is the compound of Formula 14, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 14, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 14, wherein Zis C, W is N, U is CH.

An embodiment of the disclosure is the compound of Formula 14, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 14, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the compound of Formula V-1 is of the following Formula4,

wherein R″ is O, NH,

An embodiment of the disclosure is the compound of Formula 4, whereinR^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylamino or NH₂,preferably H, OH or NH₂.

An embodiment of the disclosure is the compound of Formula 4, wherein m6is 0, 1, 2 or 3, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 4, whereinR^(1′) is O, NH,

preferably O or NH.

An embodiment of the disclosure is the compound of Formula 4, wherein R′is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy, preferablyH, halogen or C₁₋₃ fluoroalkyl, more preferably H or F.

An embodiment of the disclosure is the compound of Formula 4, wherein mis 0, 1, 2, 3 or 4, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 4, wherein R″is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylaminoor C₁₋₃ alkylamino, preferably H, halo, methylamino, dimethylamino,cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

An embodiment of the disclosure is the compound of Formula 4, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 4, wherein Zis C, U is 0 or S, W is CH.

An embodiment of the disclosure is the compound of Formula 4, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 4, wherein Zis C, U is CH, W is N.

An embodiment of the disclosure is the compound of Formula 4, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 4, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 4 having thestructure as shown in Formula 4-1,

In Formula 4-1, R^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino or NH₂; Y₁ is CH₂ or

R^(1′) is O, NH,

R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino orC₃₋₅ heterocycloalkyl; n is 0, 1 or 2; R′ is H, halogen, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl or C₁₋₃ alkoxy; m is n is 0, 1 or 2; U is O or S; R′″ isH, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen; k is 0,1, 2, 3 or 4.

An embodiment of the disclosure is the compound of Formula 4-1, whereinR^(1′) is NH.

An embodiment of the disclosure is the compound of Formula 4-1, whereinR″ is H.

An embodiment of the disclosure is the compound of Formula 4-1, whereinR′ is H.

An embodiment of the disclosure is the compound of Formula 4-1, whereinR^(2′) is OH.

An embodiment of the disclosure is the compound of Formula 4-1, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 4, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 4, wherein Uis S.

An embodiment of the compound of Formula VI-1 is of the followingFormula 16 or 17,

wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R^(1′) is O, NH,

An embodiment of the disclosure is the compound of Formula 16, whereinm2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

An embodiment of the disclosure is the compound of Formula 16, whereinR^(1′) is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 16, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, halogen or C₁₋₃ fluoroalkyl, more preferably H or F.

An embodiment of the disclosure is the compound of Formula 16, wherein mis 0, 1, 2, 3 or 4, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 16, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₁₋₃ alkylamino, preferably H, halo, methylamino,dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F ordimethylamino.

An embodiment of the disclosure is the compound of Formula 16, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 16, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 16, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 16, wherein Zis C, U is CH, W is N.

An embodiment of the disclosure is the compound of Formula 16, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 16, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 17, whereinm2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

An embodiment of the disclosure is the compound of Formula 17, whereinR″ is O, NH,

preferably NH.

An embodiment of the disclosure is the compound of Formula 17, whereinR′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy,preferably H, halogen or C₁₋₃ fluoroalkyl, more preferably H or F.

An embodiment of the disclosure is the compound of Formula 17, wherein mis 0, 1, 2, 3 or 4, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 17, whereinR″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₁₋₃ alkylamino, preferably H, halo, methylamino,dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F ordimethylamino.

An embodiment of the disclosure is the compound of Formula 17, wherein nis 0, 1, or 2, preferably 0 or 1.

An embodiment of the disclosure is the compound of Formula 17, wherein Zis C, U is O or S, W is CH.

An embodiment of the disclosure is the compound of Formula 17, wherein Zis N, U is CH, W is CH.

An embodiment of the disclosure is the compound of Formula 17, wherein Zis C, U is CH, W is N.

An embodiment of the disclosure is the compound of Formula 17, whereinR′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen,preferably H, F, methoxy, methylamino or dimethylamino.

An embodiment of the disclosure is the compound of Formula 17, wherein kis 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

Some embodiments of the disclosure are the compounds having a structuredepicted in Table 1, or a pharmaceutical acceptable salt, an enantiomer,a non-enantiomer, a tautomer, a racemate, a solvate, a metabolicprecursor, a prodrug thereof.

TABLE 1

159985

160273

160275

160313

160383

170350

161177

160219

170351

160744

160939

170352

161103

161104

161111

170353

161215

170354

161409

170355

170356

170357

160624

170358

170359

170450

170451

162641

162640

177031

177032

177033

177034

177035

162842

177036

177037

177038

177039

162903

170742

179143

180944

163123

184605

163365

180948

189149

180950

174251

175552

190753

139854

137955

186756

170257

185458

132159

132560

137361

180262

185563

181964

133065

138266

136767

132168

139269

113070

129071

112772

127973

123374

129975

138876

130177

133678

190279

133380

120581

161247

161598

178884

177685

178686

180187

190222

190083

129804

134555

134666

132777

133298

102291

190892

101193

180094

180095

180096

180097

180098

180099

180194

180195

180196

180199

180215

180216

180218

180219

180310

180312

180313

180314

180315

180316

180317

180318

120010

120011

120012

120013

120014

120015

120016

120017

120018

120019

123013

123014

123015

123016

123017

123018

123019

123413

123414

123415

123416

123417

123418

123419

136171

136172

136173

136174

136175

136176

136177

136178

136179

136571

136572

136573

136574

136575

136576

136577

136578

136579

139571

139572

139573

139575

139576

139577

165514

165554

165582

165802

165824

165810

165846

165950

165825

165954

165952

165923

166099

166123

166097

166136

166124

166330

166344

166362

166522

166531

166807

166879

166935

166965

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols generally identify similar components, unless contextdictates otherwise. The illustrative alternatives described in thedetailed description, drawings, and claims are not meant to be limiting.Other alternatives may be used and other changes may be made withoutdeparting from the spirit or scope of the subject matter presented here.It will be readily understood that the aspects, as generally describedherein, and illustrated in the FIGURE, can be arranged, substituted,combined, and designed in a wide variety of different configurations,all of which are explicitly contemplated and make part of thisapplication.

An embodiment is the compound wherein the compound is isotopicallylabeled or radiolabeled. An embodiment is a solvate, hydrate, salt, orester or the compound of the disclosure.

An aspect of the disclosure is a composition, comprising a compound ofthe disclosure and a pharmaceutically acceptable excipient.

An aspect of the disclosure is a method for aiding in the treatment of atauopathy in a subject, the method comprising administering an effectiveamount of a compound of the disclosure, or the composition of thedisclosure, wherein the compound or the composition treats the subject.

In some embodiments, the tauopathy is a neurodegenerative tauopathy. Insome embodiments, the tauopathy is selected from the group consisting ofAlzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS),Huntington's disease (HD), Parkinson's disease (PD), Creutzfeldt-Jacobdisease, Dementia pugilistica, Down's Syndrome,Gerstmann-Straussler-Scheinker disease, British dementia, Danishdementia, inclusion-body myositis, prion protein cerebral amyloidangiopathy, traumatic brain injury, Guam Parkinsonism-dementia complex,Non-Guamanian motor neuron disease with neurofibrillary tangles,argyrophilic grain dementia, corticobasal degeneration, diffuseneurofibrillary tangles with calcification, frontotemporal dementia,frontotemporal dementia with parkinsonism linked to chromosome 17,Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick diseasetype C, Pallido-ponto-nigral degeneration, Pick's disease, progressivesubcortical gliosis, progressive supranuclear palsy, Subacute sclerosingpanencephalitis, Tangle-only dementia, White matter tauopathy withglobular glial inclusions, Frontotemporal dementia, PostencephaliticParkinsonism, Parkinsonism linked to chromosome 17, and Myotonicdystrophy. In some embodiments, the tauopathy is Alzheimer's disease(AD), progressive supranuclear palsy (PSP), corticobasal degeneration(CBD), or Pick's disease (PiD).

In some embodiments, according to any of the methods described above,the method further comprises administering to the subject at least oneadditional therapy. In some embodiments, the at least one additionaltherapy is selected from neurological drugs, anti-Tau antibodies, Tauinhibitors, anti-amyloid beta antibodies, beta-amyloid aggregationinhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

In some embodiments, according to any of the methods described above,the subject is diagnosed as having or being at risk of developing a Tauprotein-associated disease. In some embodiments, the subject isdiagnosed as having or being at risk of developing a tauopathy selectedfrom the group consisting of Alzheimer's disease (AD), progressivesupranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick'sdisease (PiD).

In another aspect, provided herein is a method of reducing pathologicalhuman Tau in a sample. The method comprises a step of contacting thesample with a bispecific conjugate according to any of the embodimentsdescribed above. In some embodiments, the pathological human Tau is froma tauopathy selected from the group consisting of Alzheimer's disease(AD), progressive supranuclear palsy (PSP), corticobasal degeneration(CBD), and Pick's disease (PiD). In some embodiments, the pathologicalhuman Tau is Tau Type 1A, IB, 11A, or MB; misordered Tau; mis-disorderedTau; sarkosyl-insoluble Tau; an extracellular Tau deposit; a Tauaggregate; paired helical filaments; a neurofibrillary pathology; or ahyperphosphorylated form of truncated Tau or full-length Tau. In someembodiments, the pathological human Tau is hyperphosphorylated andsarkosyl-insoluble Tau. In some embodiments, the sample is a brainsample, a cerebrospinal fluid sample, or a blood sample. In someembodiments, the detecting comprising producing a readout comprisinginformation about the presence of pathological human Tau in the sample.In some embodiments, the sample is from a subject and the method furthercomprises diagnosing whether the subject has a tauopathy or is likely todevelop a tauopathy based on the readout.

In another aspect, provided herein is a method of reducing the level ofTau protein in a subject having, or at risk of developing, a Tauprotein-associated disease, comprising administering to the subject acompound according to any of the embodiments described above, or apharmaceutical composition according to any of the embodiments describedabove, wherein a) the level of non-phosphorylated Tau protein,phosphorylated Tau protein, and/or hyperphosphorylated Tau protein isreduced in the subject as compared to their levels in the subject priorto administration of the compound; and/or b) the level of a pathologicalTau species is reduced in the subject as compared to its level in thesubject prior to administration of the compound.

In another aspect, provided herein is a method of retaining orincreasing cognitive memory capacity or slowing memory loss in a subjecthaving or at risk of developing a Tau protein-associated disease,comprising administering to the subject a compound according to any ofthe embodiments described above or a pharmaceutical compositionaccording to any of the embodiments described above.

In another aspect, provided herein is a method of inhibiting and/orreversing the propagation of Tau aggregation in a subject having or atrisk of developing a Tau protein-associated disease, comprisingadministering to the subject a compound according to any of theembodiments described above or a pharmaceutical composition according toany of the embodiments described above.

In another aspect, provided herein is a method of inhibiting and/orreversing Tau seeding in a subject having or at risk of developing a Tauprotein-associated disease, comprising administering to the subject acompound according to any of the embodiments described above or apharmaceutical composition according to any of the embodiments describedabove.

Definitions

Unless otherwise defined, all terms of art, notations, and otherscientific terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the art to which thisapplication pertains. In some cases, terms with commonly understoodmeanings are defined herein for clarity and/or for ready reference, andthe inclusion of such definitions herein should not necessarily beconstrued to represent a substantial difference over what is generallyunderstood in the art. Many of the techniques and procedures describedor referenced herein are well understood and commonly employed usingconventional methodology by those skilled in the art.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number. If there areuses of the term which are not clear to persons of ordinary skill in theart, given the context in which it is used, “about” will mean up to plusor minus 10% of the particular term.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination. All combinations of the embodimentspertaining to the disclosure are specifically embraced by the presentdisclosure and are disclosed herein just as if each and everycombination was individually and explicitly disclosed. In addition, allsub-combinations of the various embodiments and elements thereof arealso specifically embraced by the present disclosure and are disclosedherein just as if each and every such sub-combination was individuallyand explicitly disclosed herein. When a range of values is listed, it isintended to encompass each value and sub-range within the range. Forexample “C₁₋₆” is intended to encompass C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆,C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆, C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆,C₄₋₅, and C₅₋₆.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having indicated number of carbon atoms. In someembodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). Insome embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”).In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms(“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbonatoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbonatom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁),ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentyl (C₅), amyl(C₅), neopentyl (C₅), 3-methyl-2-butyl (C₅), tertiary amyl (C₅), andn-hexyl (C₆).

“Alkenyl” refers to an alkyl group with one or more carbon-carbon doublebonds at any position of the chain, which can be monosubstituted orpolysubstituted, and can be monovalent, divalent or multivalent.Examples of the alkenyl group include a vinyl group, a propenyl group, abutenyl group, a pentenyl group, a hexenyl group, a butadienyl group, apentadienyl group, a hexadienyl group, etc.

“Alkynyl” refers to an alkyl group with one or more carbon-carbon triplebonds at any position of the chain, which can be monosubstituted orpolysubstituted, and can be monovalent, divalent or multivalent.Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl,etc.

“Cycloalkyl” includes any stable cyclic or polycyclic hydrocarbon groupand any carbon atom which is saturated, which can be monosubstituted orpolysubstituted, and can be monovalent, divalent or multivalent.Examples of such cycloalkyl groups include, but are not limited to,cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, etc.

“Optionally” means that an event or situation described subsequentlymay, but not necessarily, occur, and the description includes theoccurrence of the event or situation mentioned above and the absence ofthe event or situation described therein.

“Substituted” means that any one or more hydrogen atoms on a particularatom are replaced with substituents, including deuterium and hydrogenvariants, as long as the valence of a particular atom is normal and thesubstituted compound is stable. When the substituent is a keto (i.e.,═O), it means that two hydrogen atoms are substituted. Ketonesubstitution does not occur on aromatic groups. The term “optionallysubstituted” means that it may or may not be substituted. Unlessotherwise specified, the type and number of substituents may bearbitrary on the basis of being chemically achievable.

When any variable (e.g. R) occurs more than one time in any constituentsor formula for a compound, its definition at each occurrence isindependent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted by 0-2 of R, then saidgroup may optionally be substituted by up to two R groups and R at eachoccurrence is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When the number of a bonding group is zero, for example, -(A)₀-, thenthis bonding group is a single bond.

“Alkoxy” refers to refers to said alkyl group with a specified number ofcarbon atoms attached through an oxygen bridge. Unless otherwisespecified, C₁₋₆ alkoxy includes C₁, C₂, C₃, C₄, C₅ and C₆ alkoxy group.Examples of alkoxy groups include, but are not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,n-pentyloxy and S-pentyloxy.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon substituentwhich can be monosubstituted or polysubstituted, and can be monovalent,divalent or polyvalent, and can be monocyclic or polycyclic (e.g., 1 to3 rings; at least one of which is aromatic). They are fused together orcovalently linked.

“Halo” or “halogen” by itself or as part of another substituent refersto a fluorine, chlorine, bromine or iodine atom.

“Haloalkyl” includes both monohaloalkyl and polyhaloalkyl. For example,the term “halo(C₁₋₄)alkyl” includes, but is not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,etc. Unless otherwise specified, examples of haloalkyl include, but arenot limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl.

“Heterocyclo” refers to a radical of a 3- to 10-membered non-aromaticring or aromatic ring system having indicated ring carbon atoms (such as2 to 6 ring carbon atoms) and 1 to 4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“C₂₋₆ heterocyclo”). In heterocyclo groups that contain one or morenitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. A heterocyclo group can either be monocyclic(“monocyclic heterocyclo”) or a fused, bridged or spiro ring system suchas a bicyclic system (“bicyclic heterocyclo”), and can be saturated orpartially unsaturated. Heterocyclo bicyclic ring systems can include oneor more heteroatoms in one or both rings. “Heterocyclo” also includesring systems wherein the heterocyclic ring, as defined above, is fusedwith one or more carbocyclic groups wherein the point of attachment iseither on the carbocyclic or heterocyclic ring, or ring systems whereinthe heterocyclic ring, as defined above, is fused with one or more arylor heteroaryl groups, wherein the point of attachment is on theheterocyclic ring, and in such instances, the number of ring memberscontinue to designate the number of ring members in the heterocyclicring system.

“Nitrogen protecting group” refers to a protecting group for preventingside reactions at the amino nitrogen position. Representative aminoprotecting groups include, but are not limited to formyl; acyl, such asalkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl);alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); Arylmethoxycarbonyl,such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc);arylmethyl, such as benzyl (Bn), trityl (Tr),1,1-di-(4′-methoxyphenyl)methyl; silyl groups such as trimethylsilyl(TMS) and tert-butyldimethylsilyl (TBS), etc..

In some embodiments, a heterocyclo group is a 5-10 membered non-aromaticring system or aromatic ring system having indicated ring carbon atomsand 1-4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, aheterocyclo group is a 5-6 membered non-aromatic ring system or aromaticring system having indicated ring carbon atoms and 1-4 ring heteroatoms,wherein each heteroatom is independently selected from nitrogen, oxygen,and sulfur (“5-6 membered heterocyclo”). In some embodiments, the 5-6membered heterocyclo has 1-3 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclohas 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Insome embodiments, the 5-6 membered heterocyclo has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclo groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiorenyl.Exemplary 4-membered heterocyclo groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclo groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclo groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclo groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclo groups containing one heteroatom include, withoutlimitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, andthianyl. Exemplary 6-membered heterocyclo groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclo groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclo groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl, and thiepanyl.Exemplary 8-membered heterocyclo groups containing one heteroatominclude, without limitation, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclo groups fused to a C₆ aryl ring (alsoreferred to herein as a 5,6-bicyclic heterocyclic ring) include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary6-membered heterocyclo groups fused to an aryl ring (also referred toherein as a 6,6-bicyclic heterocyclic ring) include, without limitation,tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

The term “pharmaceutically acceptable salt” means a salt that is notharmful to mammals, especially humans. Pharmaceutically acceptable saltscan be formed using non-toxic acids or bases, including mineral acids orinorganic bases, or organic acids or organic bases. Examples ofpharmaceutically acceptable salts include metal salts formed withaluminum, calcium, lithium, magnesium, potassium, sodium, zinc and soon, and organic salts formed with lysine, N, N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), procaine and so on. Also, pharmaceuticallyacceptable salts contain acid-addition salts and base-addition salts.

The term “pharmaceutically acceptable excipient” means pharmaceuticallyacceptable materials, compositions, or vehicles such as physiologicalsaline solutions, liquid or solid fillers, diluents, solvents, orencapsulants. Examples of pharmaceutically acceptable excipients includewater, saline water, physiological saline water or phosphate bufferedsaline water (PBS), sodium chloride injection solution, Ringer'sinjection solution, isotonic dextrose injection solution, sterile waterinjection solution, dextrose, and lactated Ringer's injection solution.

“Effective amount” means enough amount of medicine or agent which canachieve the desired affect without toxin. For the oral preparation inthis invention, “effective amount” of a kind of active substance incompositions means the amount needed to achieve the desired affect whencombining with another active substance in compositions. The effectiveamount varies with each individual, and depends on ages of receptors andgeneral situations, also specific active substances.

The term “solvate” means a solvent-containing compound that is formed byassociation of one or a plurality of solvent molecules to the compoundsof the present invention. Solvates include, for example, monosolvates,disolvates, trisolvates, and tetrasolvates. Also, solvates includehydrates. The term “hydrate” means a compound further containing astoichiometric or a non-stoichiometric amount of water constrained bynon-covalent bonding intermolecular force, or a salt thereof. Hydratesinclude monohydrates, dihydrates, trihydrates, tetrahydrates, and thelike.

The term “effective dose” refers to the amount of a compound or acomposition which will have a targeted effect. For example, in someembodiments, the effective dose may refer to the amount of a compound ora composition which will enable tau imaging.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease. In some embodiments, treatment is administered after one ormore signs or symptoms of the disease have developed or have beenobserved. In other embodiments, treatment may be administered in theabsence of signs or symptoms of the disease. For example, treatment maybe administered to a susceptible subject prior to the onset of symptoms(for example, in light of a history of symptoms or a known geneticpredisposition). Treatment may also be continued after symptoms haveresolved, for example, to delay or prevent recurrence.

The compounds of the present invention can be prepared by a variety ofsynthetic methods well known to those skilled in the art, including theembodiments listed below, combinations thereof with other chemicalsynthesis methods, and equivalent alternatives known to those skilled inthe art. Preferred embodiments include, but are not limited to, theembodiments of the invention.

Synthesis of Compounds:

The following synthetic procedures are provided as examples, using whichone of ordinary skill in the art can synthesize the compounds of thedisclosure.

Compounds of Formula (I)

Compounds of the general formula (I) are prepared as set forth in theScheme below:

Compounds of Formula (II)

Compounds of the general formula (II) are prepared as set forth in theScheme below:

Compounds of Formula (III)

Compounds of the general formula (III) are prepared as set forth in theScheme below:

Compounds of Formula (IV)

Compounds of the general formula (IV) are prepared as set forth in theScheme below:

Compounds of Formula (V)

Compounds of the general formula (V) are prepared as set forth in theScheme below:

Compounds of Formula (VI)

Compounds of the general formula (VI) are prepared as set forth in theScheme below:

Other compounds within the scope of the disclosure are synthesized bymethods like these, and by analogy with methods set forth in theExamples below. Additional synthetic methods can be found inWO2019214681, WO2018102067 and WO2019014429, all of which areincorporated herein by reference in full.

Methods of Treatment

Compounds of the disclosure are administered to a subject in order totreat a tauopathy, a disorder or disease associated with theaccumulation of tau protein aggregates and/or neurofibrillary tangles.Tauopathies include Alzheimer's Disease (AD), amyotrophic lateralsclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD),Creutzfeldt-Jacob disease, Dementia pugilistica, Down's Syndrome,Gerstmann-Straussler-Scheinker disease, British dementia, Danishdementia, inclusion-body myositis, prion protein cerebral amyloidangiopathy, traumatic brain injury, Guam Parkinsonism-dementia complex,Non-Guamanian motor neuron disease with neurofibrillary tangles,argyrophilic grain dementia, corticobasal degeneration, diffuseneurofibrillary tangles with calcification, frontotetemporal dementia,frontotemporal dementia with parkinsonism linked to chromosome 17,Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick diseasetype C, Pallido-ponto-nigral degeneration, Pick's disease, progressivesubcortical gliosis, progressive supranuclear palsy, Subacute sclerosingpanencephalitis, Tangle-only dementia, White matter tauopathy withglobular glial inclusions, Frontotemporal dementia, PostencephaliticParkinsonism, Parkinsonism linked to chromosome 17, and Myotonicdystrophy. In some embodiments, the tauopathy is Alzheimer's disease(AD), progressive supranuclear palsy (PSP), corticobasal degeneration(CBD), and Pick's disease (PiD).

A. Administration

After formulation with an appropriate pharmaceutically acceptableexcipient in a desired dosage, the pharmaceutical compositions of thisinvention can be administered to humans and other animals orally,parenterally, intracisternally, intraperitoneally, intrathecally,intraventricularly, topically, bucally, or the like, depending on thedisease or condition being treated.

In certain embodiments, a pharmaceutical composition comprising acompound of the disclosure is administered orally or parenterally, atdosage levels sufficient to deliver from about 0.001 mg/kg to about 200mg/kg in one or more doses for one or several days. In some embodiments,the effective amount per dose varies from about 0.001 mg/kg to about 200mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kgto about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic and/or prophylactic effect. In some embodiments, thecompounds described herein are at dosages sufficient to deliver fromabout 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, fromabout 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg toabout 25 mg/kg, of subject body weight per day, one or more times a day,to obtain the desired therapeutic and/or prophylactic effect. Thedesired dosage may be delivered three times a day, twice a day, once aday, every other day, every third day, every week, every two weeks,every three weeks, or every four weeks. In some embodiments, the dosageis delivered using multiple administrations (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or more administrations). In some embodiments, the composition describedherein is administered at a dose that is below the dose at which theagent causes non-specific effects.

In some embodiments, at least one additional therapy is administered tothe subject. In some embodiments, the additional therapy is aneurological drug, anti-Tau antibody, Tau inhibitor, anti-amyloid betaantibody, beta-amyloid aggregation inhibitor, anti-BACE1 antibody, orBACE1 inhibitor.

In some embodiments, the subject is diagnosed as having or being at riskof developing a Tau protein-associated disease. In some embodiments, thesubject is diagnosed as having or being at risk of developing atauopathy selected from the group consisting of Alzheimer's disease(AD), progressive supranuclear palsy (PSP), corticobasal degeneration(CBD), and Pick's disease (PiD).

B. Compositions

Pharmaceutical compositions described herein can be prepared by methodsgenerally known in the art of pharmacology. In general, such methodsinclude the steps of combining the compound of the disclosure with acarrier and/or one or more other accessory ingredients, and then shapingand/or packaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage, such as, for example, one-half orone-third of such a dosage.

Pharmaceutically acceptable excipients used in the manufacture ofpharmaceutical compositions include inert diluents, dispersing and/orgranulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, stabilizers,buffering agents, lubricating agents, and/or oils. Excipients such ascocoa butter and suppository waxes, coloring agents, coating agents,sweetening, flavoring, and perfuming agents may also be present in thecomposition.

Suitable diluents include calcium carbonate, sodium carbonate, calciumphosphate, calcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Suitable granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof

C. Kits

In some embodiments, a kit described herein further includesinstructions for using the kit. A kit described herein may also includeinformation as required by a regulatory agency such as the U.S. Food andDrug Administration (FDA). In some embodiments, the information includedin the kits is prescribing information. In some embodiments, the kitsand instructions provide for treating a disease (e.g., neurologicaldisorder, neurodegenerative disease, or tauopathy) in a subject in needthereof. In some embodiments, the kits and instructions provide forpreventing a disease (e.g., neurological disorder, neurodegenerativedisease, or tauopathy) in a subject in need thereof. In certainembodiments, the kits and instructions provide for reducing the risk ofdeveloping a disease (e.g., neurological disorder, neurodegenerativedisease, or tauopathy) in a subject in need thereof. In someembodiments, the kits and instructions provide for promoting thedegradation of tau protein in a subject or cell. A kit described hereinmay include one or more additional pharmaceutical agents describedherein as a separate composition.

All publications and patent applications mentioned in this disclosureare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

No admission is made that any reference cited herein constitutes priorart. The discussion of the references states what their authors assert,and the inventors reserve the right to challenge the accuracy andpertinence of the cited documents. It will be clearly understood that,although a number of information sources, including scientific journalarticles, patent documents, and textbooks, are referred to herein; thisreference does not constitute an admission that any of these documentsforms part of the common general knowledge in the art.

The discussion of the general methods given herein is intended forillustrative purposes only. Other alternative methods and alternativeswill be apparent to those of skill in the art upon review of thisdisclosure, and are to be included within the spirit and purview of thisapplication.

EXAMPLES

The following examples are provided as a further guide for those ofordinary skill in the art, and are not intended to limit the scope ofthe claimed invention in any way.

In general in the examples below, chemicals were purchased fromSinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or othervendors. ¹H NMR and ¹⁹F NMR spectra were recorded on a Bruker AVIII 400or Bruker AVIII 500 spectrometer.

LCMS measurement was run on an Agilent 1200 HPLC/6100 SQ System usingthe following conditions: Method A: Mobile Phase: A: Water (0.01% TFA)B: CAN (0.01% TFA); Gradient Phase: 5% B increasing to 95% B within 1.4min, 95% B with 1.6 min (total runtime: 3 min); Flow Rate: 2.3 mL/min;Column: SunFire C18, 4.6*50 mm, 3.5 μm; Column Temperature: 50° C.Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API. Method B: MobilePhase: A: Water (10 mM NH₄HCO₃) B: Acetonitrile; Gradient Phase: 5% to95% B within 1.5 min, 95% B with 1.5 min (total runtime: 3 min); FlowRate: 2.0 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm; ColumnTemperature: 40° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD(ES-API). Method C: Mobile Phase: A: Water (10 mM NH₄HCO₃) B:Acetonitrile; Gradient Phase: 5% to 95% B within 1.5 min, 95%B with 1.5min (total runtime: 3 min); Flow Rate: 2.0 mL/min; Column: XBridge C18,4.6*50 mm, 3.5 p.m; Column Temperature: 40° C. Detectors: ADC ELSD, DAD(214 nm and 254 nm), MSD (ES-API).

Abbreviations: THF—tetrahydrofuran; DMF—N,N-dimethylformamide;EtOAc—ethyl acetate; DCM—dichloromethane; MeOH—methanol; EtOH—ethanol;TEA—triethanolamine; TFA—trifluoroacetic acid; RT—room temperature.

Additional embodiments are disclosed in further detail in the followingexamples, which are provided by way of illustration and are not in anyway intended to limit the scope of this disclosure or the claims. Whileparticular alternatives of the present disclosure have been disclosed,it is to be understood that various modifications and combinations arepossible and are contemplated within the true spirit and scope of theappended claims. There is no intention, therefore, of limitations to theexact abstract and disclosure herein presented.

Example 1: Synthesis of Compound 159985

(A)2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methyl-benzenesulfonate: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]carbamate(500 mg, 1.12 mmol) in DMF (10 mL) was added with NaH (107.49 mg, 4.48mmol) at 0° C. and stirred at RT for 1 h.2-[2-[2-[2-[2-[2-(4-methyl-phenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (2.65 g, 4.48 mmol) in DMF (10 mL) was added tothe reaction mixture and stirred at RT for 14 h. The mixture wasquenched by adding water at 0° C. and then extracted with EtOAc (200mL). The organic layer was washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, concentrated and purified by column chromatography(DCM:MeOH=10:1, Rf=0.7) to give2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzene-sulfonate (compound 159835, 603 mg, 0.70 mmol, 62%yield) as a pale-yellow solid.

(B) tent-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate:A mixture of2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzene-sulfonate (200 mg, 0.23 mmol) and NaI (42 mg, 0.28 mmol)in CH₃CN (5 mL) was heated at 80° C. for 20 h. The residue was taken upin DCM (50 mL) and water (50 mL). The organic layer was washed withwater (50 mL), brine (50 mL) dried over Na₂SO₄ and concentrated to givetert-butylN4-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzo-thiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(compound 159890, 185.1 mg, 0.23 mmol, 98% yield) as a yellow solid.

(C) tent-butylN-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]carbamate:A mixture of2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (67 mg,0.24 mmol), K₂CO₃ (51 mg, 0.37 mmol) and tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(100 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Themixture was quenched with water and then extracted with DCM (200 mL).The organic layer was dried over Na₂SO₄, concentrated, and purified bycolumn chromatography on silica gel (DCM:MeOH=20:1, Rf=0.52) to givetert-butylN-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(53 mg, 0.05 mmol, 45% yield) as a pale-yellow solid.

(D)2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)-pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]isoindole-1,3-dione:To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)-piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(52 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.08 mL, 1.08 mmol) andstirred at RT for 20 h. The mixture was poured into ice water andneutralized with sat. NaHCO₃ solution to pH 8. The residue was taken upin DCM (20 mL) and water (10 mL). The organic layer was washed withwater (10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated todryness to give2-[2,6-bis(oxo)-piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzo-thiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione(compound 159985, 41 mg, 0.05 mmol, 83% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆). MS (ESI) m/z 867 (M+H)⁺.

Example 2: Synthesis of Compound 160219

(A) Compound 160087: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at0° C. and stirred at room temperature for 1 h.2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(1.86 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture andstirred at room temperature for 14 h. The mixture was cooled to 0° C.and quenched with water. The precipitation was collected by filtration,washed with water and purified by column chromatography (DCM:MeOH=20:1,Rf=0.68) to give2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (595 mg, 0.86 mmol, 77% yield) as a yellowsolid.

(B) Compound 160150: A mixture of2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (595 mg, 0.86 mmol), NaI (156 mg, 1.04 mmol) inMeCN (15 mL) was heated at 80° C. for 17 h. The residue was taken up inDCM (50 mL) and water (50 mL). The organic layer was washed with water(50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated to givetert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzo-thiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(449 mg, 0.70 mmol, 81% yield) as a yellow solid.

(C) Compound 160159: A mixture of2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (96 mg,0.35 mmol), K₂CO₃ (96 mg, 0.70 mmol), tert-butylN-[2-[4-[6-(di-methylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(150 mg, 0.23 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Water(10 mL) was added to the mixture and the resulting precipitation wascollected by filtration. The residue was purified by columnchromatography (DCM:EtOAc=5:2, Rf=0.32) to give tert-butylN-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]-oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-carbamate(121 mg, 0.15 mmol, 66% yield) as a yellow solid.

(D) Compound 160219: To a solution of tert-butylN-[2-[2-[2-[2,6-bis-(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(120 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.23 mL, 3.03 mmol),and the mixture stirred at room temperature for 20 h. The mixture waspoured into ice water and neutralized with sat. NaHCO₃ to pH 8. Theresidue was taken up in DCM (20 mL) and water (10 mL). The organic layerwas washed with water (10 mL), brine (10 mL), dried over Na₂SO₄, andconcentrated to dryness to give2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione(21 mg, 0.03 mmol, 18% yield) as a yellow solid.

Example 3: Synthesis of Compound 160939

(A) Compound 160812: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at0° C. and stirred at RT for 1 h.2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (1125 mg, 2.24 mmol) in DMF (5 mL) was added tothe reaction mixture and stirred at RT for 22 h. The mixture was takenup in water (50 mL) and DCM (50 mL). The organic layer was washed withwater (50 mL), brine (50 mL) dried over Na₂SO₄, concentrated andpurified by column chromatography on silica gel (EtOAc:DCM=1:5, Rf=0.13)to give2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]-amino]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (733 mg, 0.94 mmol, 84% yield) as a yellowsolid.

(B) Compound 160829: A mixture of2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]-ethoxy]ethyl4-methylbenzenesulfonate (333 mg, 0.43 mmol) and NaI (109 mg, 0.73 mmol)in CH₃CN (10 mL) was heated at 80° C. for 15 h. The solvent was removedby vacuo and the residue was re-dissolved in EtOAc. The mixture waswashed with water (50 mL), brine (50 mL), dried over MgSO₄ andconcentrated to give tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]carbamate(112 mg, 0.15 mmol, 36% yield) as a yellow solid.

(C) Compound 160889: A mixture of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-3a,7a-dihydro-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]-carbamate(112 mg, 0.15 mmol), Cs₂CO₃ (149.09 mg, 0.46 mmol) and dimethyl4-hydroxy-benzene-1,2-dicarboxylate (64 mg, 0.30 mmol) in DMF (2 mL) wasstirred at 50° C. for 1 h. The mixture was cooled to RT and added withwater. The precipitation was collected by filtration and then purifiedby column chromatography (EtOAc:DCM=1:1, Rf=0.33) to give dimethyl4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzo-thiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]-ethoxy]benzene-1,2-dicarboxylate(102 mg, 0.13 mmol, 82% yield) as a yellow solid.

(D) Compound 160901: To a solution of dimethyl4-[2-[2-[2-[2-[[2-[4-[6-(dimethyl-amino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]-ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate(102 mg, 0.13 mmol) in EtOH (2 mL) was added NaOH (40 mg, 1 mmol) inwater (2 mL). The resulting mixture was stirred at RT for 40 h. Thereaction was diluted with EtOAc (10 mL) and acidified with 1N HClsolution to pH 1. The organic layer was washed with water (10 mL), brine(10 mL) dried over Na₂SO₄ and concentrated to dryness to give4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalicacid (86 mg, 0.13 mmol, 99.9% yield) as an orange solid.

(E) Compound 160939: A mixture of4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalicacid (122 mg, 0.18 mmol) and 3-aminopiperidine-2,6-dione hydrochloride(32 mg, 0.20 mmol) in pyridine (5 mL) was heated at 120° C. for 19 h.The mixture was cooled to RT, diluted with DCM (100 mL) and washed withwater (50 mL) and brine (50 mL). The organic layer was collected, driedover Na₂SO₄, concentrated and purified by column chromatography(MeOH:DCM=1:10, Rf=0.73) to afford2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione(49 mg, 0.06 mmol, 35% yield) as a yellow solid.

Example 4: Synthesis of Compound 161103

(A) Compound 160891: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at0° C. and stirred at RT for 1 h. 5-(4-methylphenyl)sulfonyloxypentyl4-methylbenzenesulfonate (1.85 g, 4.48 mmol) in DMF (10 mL) was added tothe reaction mixture and stirred at RT for 17 h. The mixture was cooledto 0° C. and quenched with water. The resulting precipitation wascollected by filtration and purified by column chromatography(DCM:EtOAc=4:1, Rf=0.7) to give5-[[2-[4-[6-(dimethylamino)-pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl4-methylbenzenesulfonate (604 mg, 0.88 mmol, 79% yield) as a yellowsolid.

(B) Compound 160938: A mixture of dimethyl4-hydroxybenzene-1,2-dicarboxylate (122 mg, 0.58 mmol), Cs₂CO₃ (285 mg,0.87 mmol), KI (5 mg, 0.03 mmol) and5-[[2-[4-[6-(di-methylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]-amino]pentyl4-methylbenzenesulfonate (200 mg, 0.29 mmol) in DMF (2 mL) was heated at50° C. for 2 h. The reaction was quenched with water. The resultingsolid was collected by filtration and washed with water to give dimethyl4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]benzene-1,2-dicarboxylate(206 mg, 0.28 mmol, 98% yield) as a yellow solid.

(C) Compound 160999: A solution of dimethyl4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]-pentoxy]benzene-1,2-dicarboxylate(100 mg, 0.14 mmol) in EtOH (2 mL) was added NaOH (110 mg, 2.76 mmol) inwater (2 mL) and stirred at RT for 40 h. The reaction was neutralized topH 1 with 1N HCl solution. The precipitation was collected by filtrationand washed with water to afford4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalicacid (93 mg, 0.13 mmol, 97% yield) as a yellow solid.

(D) Compound 161054: A mixture of4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalicacid (93 mg, 0.13 mmol), and 3-aminopiperidine-2,6-dione hydrochloride(48 mg, 0.29 mmol) in pyridine (3 mL) was heated at 120° C. for 40 h.Water was then added to the mixture. The precipitate was collected byfiltration and purified by column chromatography (DCM:EtOAc=4:1,Rf=0.28) to afford tert-butylN-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(61 mg, 0.08 mmol, 58% yield) as a yellow solid.

(E) Compound 161103: A solution of tert-butylN-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(61 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.12 mL, 1.55 mmol) andstirred at RT for 6 h. The mixture was poured into iced water andneutralized with sat. NaHCO₃ solution to pH 8. The residue was taken upin DCM (20 mL) and water (10 mL). The organic layer was washed withwater (10 mL), brine (10 mL), dried over Na₂SO₄, and concentrated todryness to give2-[2,6-bis(oxo)piperidin-3-yl]-5-[5-[[2-[4-[6-(dimethylamino)-pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]pentoxy]isoindole-1,3-dione(44 mg, 0.06 mmol, 80% yield) as a yellow solid.

Example 5: Synthesis of Compound 160273

(A) Compound 160210: A mixture of3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (95 mg, 0.37mmol), K₂CO₃ (101 mg, 0.73 mmol), tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Themixture was quenched with water and extracted with DCM (200 mL). Theorganic layer was collected, dried over Na₂SO₄, concentrated andpurified by column chromatography (DCM:MeOH=20:1, Rf=0.48) to givetert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]-oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(83 mg, 0.09 mmol, 36% yield) as a pale-yellow solid.

(B) Compound 160273: To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis-(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(83 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.13 mL, 1.74 mmol) andstirred at RT for 7 h. The mixture was poured into ice water andneutralized with sat. NaHCO₃ solution to pH 8. The residue was taken upin DCM (20 mL) and water (10 mL). The organic layer was washed withwater (10 mL), brine (10 mL) dried over Na₂SO₄ and concentrated todryness to give3-[6-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-amino]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione(73 mg, 0.08 mmol, 92% yield) as a yellow solid.

Example 6: Synthesis of Compound 160313

(A) Compound 160284: A mixture of3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)-piperidine-2,6-dione (58 mg, 0.22mmol), K₂CO₃ (61 mg, 0.44 mmol), tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(95 mg, 0.15 mmol) in DMF (2 mL) was heated at 50° C. for 5 h. Water (10mL) was added to the mixture. The resulting precipitate was collected byfiltration and then purified by column chromatography (DCM:MeOH=20:1,Rf=0.52) to give tert-butylN-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]-ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(57 mg, 0.07 mmol, 50% yield) as a yellow solid.

(B) Compound 160313: To a solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(54 mg, 0.07 mmol) in DCM (5 mL) was added TFA (0.11 mL, 1.39 mmol), andthe mixture stirred at room temperature for 20 h. The mixture was pouredinto ice water and neutralized with sat. NaHCO₃ solution to pH 8. Theresidue was taken up in DCM (20 mL) and water (10 mL). The organic layerwas washed with water (10 mL), brine (10 mL), dried over Na₂SO₄, andconcentrated to dryness to give3-[6-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione(39 mg, 0.05 mmol, 77% yield) as a yellow solid.

Example 7: Synthesis of Compound 162640

Compound 162640 were synthesized according to methods similar to Example6.

¹H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.24 (d, J=2.3Hz, 1H), 8.01-8.05 (m, 4H), 7.72 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz,1H), 7.52 (d, J=9.7 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.05-7.09 (m, 2H),6.81-6.85 (m, 2H), 6.61 (t, J=5.8 Hz, 1H), 5.07 (dd, J=13.2, 5.1 Hz,1H), 4.36 (d, J=17.2 Hz, 1H), 4.19-4.27 (m, 4H), 3.79-3.85 (m, 7H), 3.66(t, J=5.8 Hz, 3H), 3.48-3.54 (m, 3H), 2.85-2.93 (m, 1H), 1.92-1.99 (m,1H).

Example 8: Synthesis of Compound 162842

Compound 162842 were synthesized according to methods similar to Example6.

¹H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.40(s, 1H), 8.13 (d, J=6.6 Hz, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.89 (dd,J=8.9, 2.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.19(s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.75 (d, J=8.9Hz, 1H), 6.70 (d, J=7.4 Hz, 1H), 5.06 (dd, J=13.2, 5.1 Hz, 1H),4.35-4.38 (m, 2H), 4.32 (d, J=17.2 Hz, 1H), 4.28 (dd, J=8.2, 4.5 Hz,2H), 4.20 (d, J=17.2 Hz, 1H), 3.96-3.99 (m, 2H), 3.92-3.95 (m, 2H), 3.08(s, 7H), 2.85-2.93 (m, 1H), 2.26-2.37 (m, 2H), 1.91-1.98 (m, 2H).

Example 9: Synthesis of Compound 162903

Compound 162903 were synthesized according to methods similar to Example6.

¹H NMR (600 MHz, DMS-d6) δ 10.97 (s, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.12(s, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.03 (dd, J=8.9, 2.6 Hz, 1H), 7.99 (d,J=8.9 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.63 (d,J=8.4 Hz, 1H), 7.18-7.21 (m, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 6.79 (d,J=8.8 Hz, 1H), 5.08 (dd, J=13.4, 5.1 Hz, 1H), 4.38 (d, J=17.2 Hz, 1H),4.22-4.29 (m, 4H), 3.89 (dd, J=9.2, 5.0 Hz, 3H), 3.11 (s, 3H), 2.56-2.63(m, 1H), 2.33-2.40 (m, 1H).

Example 10: Synthesis of Compound 163123

Compound 163123 were synthesized according to methods similar to Example6.

¹H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.06(d, J=8.4 Hz, 2H), 7.92-7.96 (m, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.74 (d,J=2.5 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.13-7.18 (m, 2H), 7.07 (dd,J=8.4, 2.1 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 5.07 (dd, J=13.4, 5.2 Hz,1H), 4.35 (d, J=17.1 Hz, 1H), 4.22-4.27 (m, 6H), 3.85-3.91 (m, 5H), 3.10(s, 7H), 2.85-2.96 (m, 1H), 2.55-2.63 (m, 2H), 2.31-2.42 (m, 2H).

Example 11: Synthesis of Compound 163365

Compound 163365 were synthesized according to methods similar to Example6.

¹H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.57 (d, J=2.5 Hz, 1H), 8.16(d, J=8.4 Hz, 2H), 8.09 (s, 1H), 7.96 (dd, J=8.9, 2.4 Hz, 1H), 7.86 (d,J=8.4 Hz, 2H), 7.68 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d,J=2.1 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.02 (dd, J=8.7,2.2 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 5.07 (dd, J=13.3, 5.2 Hz, 1H), 4.36(d, J=17.2 Hz, 1H), 4.22-4.28 (m, 5H), 3.86-3.91 (m, 3H), 3.10 (s, 5H),2.84-2.94 (m, 2H).

Example 12: Synthesis of Compound 161247

(A) Compound 161084: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(200 mg, 0.45 mmol) in DMF (3 mL) was added NaH (32 mg, 1.34 mmol) at 0°C. The resulting mixture was stirred at RT for 1 h.

2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (454 mg, 0.90 mmol) was added to the reactionmixture and stirred at RT for 22 h. The mixture was quenched with water.The precipitation was collected by filtration and purified by columnchromatography (EtOAC:DCM=2:3, Rf=0.48) to give tert-butylN-[2-[2-[2-[2-[2-[tert-butyl-(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(235 mg, 0.30 mmol, 67% yield) as a yellow solid.

(B) Compound 161112: To a solution of tert-butylN-[2-[2-[2-[2-[2-[tert-butyl-(di-methyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-phenyl]-1,3-benzothiazol-6-yl]carbamate(235 mg, 0.30 mmol) in THF (5 mL) was added 1 M TBAF solution in THF(1.81 mL, 1.81 mmol) dropwise. The reaction mixture was stirred at RTfor 7 h. The reaction mixture was concentrated to dryness and theresidue was taken up in EtOAc (100 mL). The mixture was washed withwater (100 mL) and brine (100 mL). The organic layer was collected,dried over Na₂SO₄ and concentrated to give tert-butylN-[2-[4-[6-(dimethylamino)-pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]-ethoxy]ethyl]carbamate(200 mg, 0.30 mmol, 99.7% yield) as a yellow solid.

(C) Compound 161181: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(120 mg, 0.18 mmol) in THF (3 mL) was added NaH (9 mg, 0.36 mmol) at 0°C. and stirred for 30 min. tert-Butyl 2-bromoethanoate (0.08 mL, 0.54mmol) was then added and the mixture was heated at 50° C. for 8 h. Thesolvent was removed by vacuum. The residue was purified by columnchromatography (EtOAc:DCM=2:3, Rf=0.35) to afford tert-butyl2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate(84 mg, 0.11 mmol, 60% yield) as a yellow solid.

(D) Compound 161218: A mixture of tert-butyl2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethyl-amino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate(84 mg, 0.11 mmol) and TFA (0.12 mL, 1.61 mmol) in DCM (2 mL) wasstirred at RT for 23 h. The mixture was acidified to pH 1 with 1N HClsolution. The mixture was extracted with DCM. The organic layer waswashed with brine, dried over Na₂SO₄ and was concentrated to dryness toafford2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethyl-amino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethanoicacid (60 mg, 0.10 mmol, 89% yield) as a yellow solid.

(E) Compound 161247: A mixture of(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide(45 mg, 0.11 mmol),2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoicacid (60 mg, 0.10 mmol), DIPEA (0.03 mL, 0.14 mmol) and HATU (73 mg,0.19 mmol) in anhydrous DMF (3 mL) was stirred at RT for 18 h. Themixture was diluted with DCM, washed with water and brine, dried overNa₂SO₄, concentrated and purified by column chromatography on NH silicagel (MeOH:DCM=97:3, Rf=0.48) to giverac-(2R,4S)—N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-amino]ethoxy]ethoxy]-ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide(16 mg, 0.01 mmol, 14% yield) as a yellow solid.

Example 13: Synthesis of Compound 160275

(A) Compound 160161: To a solution of NaH (81 mg, 2.02 mmol) in DMF (1mL) was added tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-carbamate(300 mg, 0.67 mmol) in DMF (6 mL) at 0° C. and stirred at 25° C. for 30min.2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (794 mg, 1.34 mmol) in DMF (3 mL) was added tothe reaction mixture and heated at 50° C. for 2 h. The mixture wasquenched with saturated NH₄Cl solution and extracted with DCM. Theorganic layer was washed with brine, dried over MgSO₄, concentrated andpurified by column chromatography (MeOH:DCM=3:97, Rf=0.3) to afford2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (273 mg, 0.32 mmol, 47% yield) as a yellow oil.

(B) Compound 160244: A mixture of2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (270 mg, 0.31 mmol) and NaI (56.18 mg, 0.37mmol) in CH3CN (5 mL) was heated at 80° C. for 19 h. The mixture wasdiluted with DCM and extracted with water (50 mL) and brine (50 mL). Theorganic layer was dried over MgSO₄ and concentrated to dryness to affordtert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(256 mg, 0.31 mmol, 99.9% yield) as an orange oil.

(C) Compound 160252: A mixture of2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (102 mg,0.37 mmol), K₂CO₃ (77 mg, 0.56 mmol) and tert-butylN-[5-[4-[6-(di-methylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(153 mg, 0.19 mmol) in DMF (4 mL) was heated at 50° C. for 18 h. Themixture was diluted with DCM (200 mL) and extracted with water. Theorganic layer was collected, dried over MgSO₄, concentrated and purifiedby column chromatog-raphy (MeOH:DCM=5:95, Rf=0.3) to give tert-butylN-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)-piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]-phenyl]pyridin-2-yl]carbamate(61 mg, 0.06 mmol, 34% yield) as a yellow solid.

(D) Compound 160275: To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)-piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(61 mg, 0.06 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0°C. The resulting mixture was stirred at RT for 5 h. The solution wasneutralized with saturated NaHCO₃ solution at 0° C. and extracted withDCM. The organic layer was washed with brine, dried over MgSO₄,concentrated and purified by column chromatography on NH silica gel(MeOH:DCM=99:1, Rf=0.3) to afford2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione(51 mg, 0.05 mmol, 86% yield) as a yellow solid.

Example 14: Synthesis of Compound 161177

(A) Compound 161026: A mixture of dimethyl 4-hydroxyphthalate (139 mg,0.62 mmol), Cs₂CO₃ (303 mg, 0.93 mmol), tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]-phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(200 mg, 0.31 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. Themixture was quenched with water and extracted with DCM. The organiclayer was dried over MgSO₄, concentrated and purified by columnchromatography (EtOAc:Hex=1:1, Rf=0.4) to give dimethyl4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzo-thiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]-benzene-1,2-dicarboxylate(148 mg, 0.20 mmol, 66% yield) as a yellow solid.

(B) Compound 161083: To a solution of dimethyl4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate(148 mg, 0.20 mmol) in MeOH (1 mL) and water (1 mL) was added LiOH (39mg, 1.63 mmol). The reaction mixture was stirred at RT for 5 days. Thesolution was acidified with 1 N HCl to pH 4-5. The resulting precipitatewas collected by filtration, washed with water and dried over vacuo toafford4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalicacid (119 mg, 0.17 mmol, 84% yield) as a yellow solid.

(C) Compound 161115: A mixture of4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzo-thiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]-phthalicacid (119 mg, 0.17 mmol) and 3-aminopiperidine-2,6-dione hydrochloride(31 mg, 0.19 mmol) in pyridine (2 mL) was heated at 120° C. for 2 days.The mixture was concentrated to dryness and purified by columnchromatography (MeOH:DCM=5:95, Rf=0.3) to afford tert-butylN-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(39 mg, 0.05 mmol, 29% yield) as a yellow solid.

(D) Compound 161177: To a solution of tert-butylN-[2-[2-[2-[2,6-bis(oxo)-piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethyl-amino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(39 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL, 13.06 mmol) at 0°C. The resulting mixture was stirred at RT for 2 h. The solution wasneutralized with sat. NaHCO₃ solution and extracted with DCM. Theorganic layer was washed with brine, dried over MgSO₄, concentrated andpurified by chromatography (MeOH:DCM=1:99, Rf=0.1) to afford2-[2,6-bis(oxo)-piperidin-3-yl]-5-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione(11 mg, 0.02 mmol, 31% yield) as a yellow solid.

Example 15: Synthesis of Compound 160383

(A) Compound 160366: A mixture of3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (63 mg, 0.24mmol), K₂CO₃ (51 mg, 0.37 mmol), tert-butylN-[5-[4-[6-(dimethyl-amino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]-ethoxy]ethoxy]ethoxy]ethyl]carbamate(100 mg, 0.12 mmol) in DMF (2 mL) was heated at 50° C. for 3 h. Themixture was quenched with water, extracted with DCM (200 mL) dried overMgSO₄, concentrated and purified by chromatography (MeOH:DCM=5:95,Rf=0.3) to afford tert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]-phenyl]pyridin-2-yl]carbamate(26 mg, 0.03 mmol, 22% yield) as a yellow solid.

(B) Compound 160383: To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis-(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(26 mg, 0.03 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0°C. and the mixture was stirred at RT for 3 h. The solution wasneutralized with sat. NaHCO₃ solution at 0° C. and then extracted withDCM. The organic layer was washed with brine, dried over MgSO₄,concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.2) toafford3-[6-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]-phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione(9 mg, 0.01 mmol, 33% yield) as a yellow solid.

Example 16: Synthesis of Compound 160744

(A) Compound 160690: To a solution of2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol(400 mg, 1.15 mmol) in DMF (10 mL) was added NaH (184 mg, 4.59 mmol) at0° C. and stirred at RT for 1 h.2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (2 mL, 4.13 mmol) was added to the mixture andstirred at RT for 14 h under argon. The mixture was diluted with DCM (10mL), washed with water (10 mL) and brine (10 mL). The organic layer wascollected, dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM:MeOH=50:1, Rf=0.29) to give2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo-[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (520 mg, 0.68 mmol, 59% yield) as pale yellowsolid.

(B) Compound 160707: A mixture of2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (520 mg, 0.68 mmol) and NaI (122 mg, 0.81 mmol)in CH3CN (6 mL) was heated at 80° C. for 5 h. The mixture was addedwater and extracted with DCM. The organic layer was washed with water(20 mL), brine (20 mL), dried over Na₂SO₄, concentrated and purified bychromatography (MeOH:DCM=1:50, Rf=0.39) to give6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]-ethoxy]ethoxy]ethoxy]imidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine(427 mg, 0.59 mmol, 87% yield) as pale-yellow solid.

(C) Compound 160744: A mixture of2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (114 mg,0.41 mmol), Cs₂CO₃ (202 mg, 0.62 mmol) and6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine(150 mg, 0.21 mmol) in DMF (3 mL) was heated at 50° C. for 20 h. Themixture was quenched with water and the resulting precipitation wascollected by filtration. The residue was purified by columnchromatography (MeOH:DCM=1:20, Rf=0.34) to give2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethyl-amino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]-ethoxy]ethoxy]ethoxy]isoindole-1,3-dione(28 mg, 0.03 mmol, 15% yield) as brown solid.

¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.28 (s, 1H), 8.23 (d,J=2.3Hz, 1H), 7.97 (d, J=7.8, 2H), 7.87 (dd, J=10.8, 8.4Hz, 1H), 7.81(d, J=8.4Hz, 1H), 7.57 (d, J=7.8Hz, 2H), 7.50 (d, J=9.7 Hz, 1H), 7.43(d, J=2.3Hz, 1H), 7.34 (dd, J=8.4, 2.3 Hz, 1H), 7.05 (dd, J=9.7, 2.3 Hz,1H), 6.63 (dd, J=8.4, 2.0 Hz, 1H), 5.11 (dd, J=12.9, 5.5 Hz, 1H),4.25-4.32 (m, 2H), 4.06-4.14 (m, 2H), 3.74-3.79 (m, 4H), 3.47-3.63 (m,18H), 3.06 (s, 6H), 2.80-2.96 (m, 2H).

Example 17: Synthesis of Compound 161111

(A) Compound 160947: To a solution of2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol(400 mg, 1.15 mmol) in dry DMF (8 mL) was added NaH (0.14 g, 3.44 mmol)at 0° C. and stirred at RT for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(1.43 g, 3.44 mmol) was added to the mixture and stirred at the sametemperature for 16 h. The reaction was quenched with water and extractedwith DCM. The organic layer was washed with water, brine, dried overNa₂SO₄, concentrated and purified by column chromatography on silica gel(EtOAc:DCM=1:5, Rf=0.33) to give2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl4-methylbenzenesulfonate (227 mg, 0.38 mmol, 33% yield) as orange solid.

(B) Compound 160997: A mixture of dimethyl4-hydroxybenzene-1,2-dicarboxylate (161 mg, 0.77 mmol), Cs₂CO₃ (374.2mg, 1.15 mmol), KI (6 mg, 0.04 mmol) and2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl4-methylbenzenesulfonate (226 mg, 0.38 mmol) in DMF (4 mL) was heated at50° C. for 4 h. The mixture was quenched with water and the resultingprecipitation was collected by filtration and washed with water to givedimethyl4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]-phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate(212 mg, 0.34 mmol, 88% yield) as an orange solid.

(C) Compound 161006: To a solution of dimethyl4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate(211 mg, 0.34 mmol) in MeOH (2 mL) was added NaOH (443 mg, 11.08 mmol)in water (2 mL) and stirred at RT for 5 days. The reaction was dilutedwith EtOAc (50 mL) and acidified with 1 N HCl solution to pH 1. Theorganic layer was washed with water (50 mL), brine (50 mL) dried overNa₂SO₄ and concentrated to give4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]-oxyethoxy]ethoxy]phthalicacid (185 mg, 0.31 mmol, 92% yield) as a yellow solid.

(D) Compound 161111: A mixture of4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalicacid (67 mg, 0.11 mmol), and 3-aminopiperidine-2,6-dione hydrochloride(20 mg, 0.15 mmol) in pyridine (3 mL) was heated at 120° C. for 14 h.The solvent was removed by vacuum. The residue was redissolved in DCMand water was added. The resulting precipitate was collected byfiltration and purified by column chromatography (MeOH:DCM=1:100,Rf=0.19) to afford2-[2,6-bis(oxo)-piperidin-3-yl]-5-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]isoindole-1,3-dione(18 mg, 0.02 mmol, 22% yield) as a yellow solid.

Example 18: Synthesis of Compound 161215

(A) Compound 160806: To a solution of NaH (138 mg, 3.45 mmol) in DMF (2mL) was added tert-butylN-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-carbamate(500 mg, 1.15 mmol) in DMF (10 mL) at 0° C. The resulting mixture wasstirred at room temperature for 30 min.2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzene-sulfonate(954 mg, 2.30 mmol) in DMF (3 mL) was added to the reaction mixture andstirred at room temperature for 21 h. The mixture was quenched withsaturated NH₄Cl solution and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, concentrated and purified by columnchromatography (EtOAc:DCM=3:17, Rf=0.3) to afford2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methyl-propan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (339 mg, 0.50 mmol, 44% yield) as a yellowsolid.

(B) Compound 160814: A mixture of2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]-pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (339 mg, 0.50 mmol) and NaI (90 mg, 0.60 mmol)in MeCN (10 mL) was heated at 80° C. for 19 h. The mixture was added towater and extracted with EtOAc. The organic layer was washed with water(50 mL), brine (50 mL), dried over MgSO₄, concentrated, and purified bycolumn chromatography (EtOAc:DCM=1:9, Rf=0.3) to afford tert-butylN-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(197 mg, 0.31 mmol, 62% yield) as a yellow solid.

(C) Compound 161091: A mixture of dimethyl4-oxobenzene-1,2-dicarboxylate (131 mg, 0.62 mmol), Cs₂CO₃ (305 mg, 0.93mmol), tert-butylN-[6-fluoro-5-[4-(6-methoxyimidazo-[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate(197 mg, 0.31 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. Themixture was quenched with water, extracted with DCM, dried over MgSO₄,concentrated, and purified by column chromatography (EtOAc:hexane=1:1,Rf=0.3) to give dimethyl4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo-[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]-ethoxy]benzene-1,2-dicarboxylate(147 mg, 0.21 mmol, 66% yield) as a yellow solid.

(D) Compound 161105: To a solution of dimethyl4-[2-[2-[[6-fluoro-5-[4-(6-methoxy-imidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]-ethoxy]ethoxy]benzene-1,2-dicarboxylate(147 mg, 0.21 mmol) in MeOH (2 mL) was added NaOH (66 mg, 1.65 mmol) inwater (2 mL), and the mixture stirred at room temperature for 3 days.The reaction was neutralized with 1N HCl solution to pH 1. Theprecipitate was collected by filtration and washed with water to give4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]-pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]-phthalicacid (135 mg, 0.20 mmol, 96% yield) as a white solid.

(E) Compound 161183: A mixture of4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]-pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]-phthalicacid (135 mg, 0.20 mmol) and 3-aminopiperidine-2,6-dione hydrochloride(49 mg, 0.29 mmol) in pyridine (2 mL) was heated at 120° C. for 20 h.The mixture was concentrated to dryness, and purified by columnchromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) to affordtert-butylN-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxy-ethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-carbamate(47 mg, 0.06 mmol, 30% yield) as a yellow solid.

(F) Compound 161215: To a solution of tert-butylN-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(47 mg, 0.06 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol) at 0° C.,and the mixture stirred at room temperature for 2 h. The solution wasneutralized with saturated NaHCO₃ solution and extracted with DCM. Theorganic layer was washed with brine, dried over MgSO₄, concentrated andpurified by chromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) toafford2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione(17 mg, 0.02 mmol, 38% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 8.28 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.92 (d,J=8.3 Hz, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.70 (dd, J=10.3, 8.2 Hz, 1H),7.46-7.52 (m, 3H), 7.43 (d, J=2.2 Hz, 1H), 7.34 (dd, J=8.2, 2.3 Hz, 1H),7.14 (t, J=5.7 Hz, 1H), 7.01 (dd, J=10.3, 2.2 Hz, 1H), 6.49 (d, J=8.5Hz, 1H), 5.08 (dd, J=13.1, 5.3 Hz, 1H), 4.34-4.28 (m, 2H), 3.75-3.83 (m,5H), 3.62 (t, J=5.5 Hz, 2H), 3.39-3.44 (m, 2H), 2.77-2.91 (m, 1H),2.49-2.66 (m, 2).

Example 19: Synthesis of Compound 161409

Compound 161409 could be synthesized by method similar to example 19.

¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H), 8.19 (d, J=2.5Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.71 (dd,J=10.2, 8.6 Hz, 1H), 7.45-7.53 (m, 3H), 7.41 (d, J=2.0 Hz, 1H), 7.32(dd, J=8.6, 2.1 Hz, 1H), 7.13 (t, J=5.3 Hz, 1H), 7.00 (dd, J=9.7, 1.6Hz, 1H), 6.49 (d, J=9.2 Hz, 1H), 5.07 (dd, J=12.8, 5.3 Hz, 1H),4.24-4.29 (m, 2H), 3.77 (s, 3H), 3.72-3.76 (m, 2H), 3.44-3.58 (m, 20H),3.34-3.41 (m, 3H), 2.77-2.91 (m, 2H).

Example 20: Synthesis of Compound 161104

(A) Compound 160937: To a solution of tert-butyl2-[4-[6-[(2-methylpropan-2-yl)oxy-carbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]-pyridine-1-carboxylate(500 mg, 1.03 mmol) in DMF (10 mL) was added NaH (49 mg, 1.23 mmol) at0° C. and stirred at RT for 30 min.2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (789 mg, 1.34 mmol) was added to the reactionmixture and stirred at RT for 6 h. The mixture was quenched with sat.NH₄Cl solution and extracted with DCM. The organic layer was washed withbrine, dried over MgSO₄, concentrated and purified by columnchromatography (EtOAc:DCM=1:4, Rf=0.33) to afford tert-butyl2-[4-[6-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo-[2,3-c]pyridine-1-carboxylate(280 mg, 0.31 mmol, 30% yield) as pale-yellow oil.

(B) Compound 160987: A solution of dimethyl4-hydroxybenzene-1,2-dicarboxylate (130.05 mg, 0.62 mmol), Cs₂CO₃ (303mg, 0.93 mmol), and tert-butyl2-[4-[6-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate(280 mg, 0.31 mmol) in DMF (3 mL) was heated at 50° C. for 3 h. Themixture was quenched with water and the resulting precipitation wascollected by filtration. The solid was then purified by columnchromatography (EtOAc:DCM=4:1, Rf=0.32) to provide dimethyl4-[2-[2-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]-pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate(98 mg, 0.10 mmol, 34% yield) as pale-yellow oil.

(C) Compound 161004: To a solution of dimethyl4-[2-[2-[2-[2-[2-[2-[(2-methyl-propan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-di-carboxylate(98 mg, 0.10 mmol) in EtOH (5 mL) was added NaOH (33 mg, 0.83 mmol) inwater (5 mL) and stirred at RT for 4 days. The reaction was diluted withDCM (10 mL) and acidified with 1 N HCl solution to pH 1. The organiclayer was washed with water (10 mL), brine (10 mL) dried over Na₂SO₄ andconcentrated to dryness to give4-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methyl-propan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-ethoxy]ethoxy]ethoxy]ethoxy]phthalicacid (79 mg, 0.10 mmol, 93% yield) as pale-yellow solid.

(D) Compound 161045: A mixture of4-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methyl-propan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-ethoxy]ethoxy]ethoxy]ethoxy]phthalicacid (79 mg, 0.10 mmol) and 3-aminopiperidine-2,6-dione HCl (18 mg, 0.11mmol) in pyridine (3 mL) was heated at 120° C. for 42 h. The solvent wasremoved in vacuo. The residue was re-dissolved in with DCM (10 mL),washed with brine, dried over Na₂SO₄, concentrated and purified bycolumn chromatography (MeOH: DCM=1:19, Rf=0.3) to give tert-butyl2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)-isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo-[2,3-c]pyridine-1-carboxylate(22 mg, 0.02 mmol, 25% yield) as a yellow solid.

(E) Compound 161104: To a solution of tert-butyl2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-bis-(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate(22 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.03 mL, 0.36 mmol), andthe mixture stirred at RT for 42 h. The mixture was neutralized withsat. NaHCO₃ to pH 8 and extracted with DCM (10 mL). The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated to dryness togive2-[2,6-bis(oxo)-piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]-amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione(15 mg, 0.02 mmol, 73% yield) as a yellow solid.

Example 21: Synthesis of Compound 160624

Compound 160557: A mixture of3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (169mg, 0.65 mmol), Cs₂CO₃ (317 mg, 0.97 mmol), tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate(209 mg, 0.32 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. Themixture was quenched with water, extracted with DCM, dried over MgSO₄,concentrated and purified by column chromatography (solvent gradient 0%to 3% MeOH in DCM, Rf=0.2) to give tert-butyl(5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate(68 mg, 0.09 mmol, 27% yield) as a yellow solid.

Compound 160624: To a solution of tert-butyl(5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate(68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL, 13.06 mmol) at 0°C. and stirred at room temperature for 6 h. The solution was neutralizedwith saturated NaHCO₃ solution at 0° C. and the solution was extractedwith DCM. The organic layer was washed with brine, dried over MgSO₄ andconcentrated to dryness to afford1-(2-(2-((5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)amino)ethoxy)ethyl)-3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione(51 mg, 0.07 mmol, 85% yield) as a yellow solid.

Example 22: Synthesis of Compound 162641

Compound 162586: A solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate(100 mg, 0.16 mmol) in DMF (5 mL) was added3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (48mg, 0.19 mmol) and K₂CO₃ (101 mg, 0.31 mmol) and heated at 80° C. for 3h. The mixture was diluted with DCM, washed with water and brine, driedover Na₂SO₄, concentrated and purified by column chromatography(MeOH:DCM=1:20, Rf=0.3) to give tert-butylN-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(70 mg, 0.09 mmol, 58% yield) as a yellow solid.

Compound 162641: To a solution of tert-butylN-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(70 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.1 mL, 1.35 mmol) andstirred at room temperature for 20 h. The mixture was neutralized withsat. NaHCO₃ solution to pH 8. The residue was taken up in DCM (20 mL)and water (10 mL). The organic layer was washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄ and concentrated to give3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-1-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethyl]piperidine-2,6-dione(30 mg, 0.04 mmol, 46% yield) as a yellow solid.

Example 23: Synthesis of Compound 161598

Compound 161444: To a solution of tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(200 mg, 0.45 mmol) in DMF (5 mL) was added NaH (43 mg, 1.79 mmol) at 0°C. and stirred at room temperature for 1 h. The mixture was added2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (681 mg, 1.34 mmol) and stirred at the sametemperature for 24 h. The reaction was quenched by adding water. Theresulting solid was collected by filtration and purified by columnchromatography (EtOAc:DCM=7:3, Rf=0.4) to give tert-butylN-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(252 mg, 0.32 mmol, 72% yield) as a yellow oil.

Compound 161467: A solution of tert-butylN-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(252 mg, 0.32 mmol) in THF (5 mL) was added TBAF (1M in THF, 1.94 mL,1.94 mmol) dropwise and stirred at room temperature for 19 h. Thereaction mixture was concentrated to dryness and the residue was takenup in EtOAc (50 mL). The mixture was washed with water (50 mL) and brine(50 mL), dried over Na₂SO₄. And concentrated to dryness to givetert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(214 mg, 0.32 mmol, 99% yield) as a yellow oil.

Compound 161530: A mixture of tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(214 mg, 0.32 mmol) and tert-butyl 2-bromanylethanoate (0.14 mL, 0.96mmol) in THF (3 mL) was added NaH (19 mg, 0.80 mmol) at 0° C. andstirred at room temperature for 42 h. The reaction was quenched byadding water. The mixture was diluted with DCM (50 mL), washed withwater (50 mL) and brine (50 mL), dried over Na₂SO₄, concentrated todryness and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.35)to afford tert-butyl2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate(130 mg, 0.17 mmol, 52% yield) as a yellow oil.

Compound 161586: To a solution of tert-butyl2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate(130 mg, 0.17 mmol) in DCM (2mL) was added TFA (0.38 mL, 4.99 mmol) andstirred at room temperature for 22 h. The mixture was concentrated todryness to afford2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoicacid TFA salt (179 mg,0.29 mmol, >99% yield) as an orange oil.

Compound 161598: A mixture of(2S,4R)-1-[(2S)-2-azanyl-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide(79 mg, 0.18 mmol),2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoicacid (104 mg, 0.17 mmol), DIPEA (0.04 mL, 0.25 mmol) and HATU (127 mg,0.33 mmol) in anhydrous DMF (3 mL) was stirred at room temperature for18 h. The mixture was taken up in DCM, washed with water and brine,dried over anhydrous Na₂SO₄, concentrated and purified by columnchromatography (MeOH:DCM=3:100, Rf=0.32) to give rac-(2R,4S)—N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide(16 mg, 0.01 mmol, 8% yield) as a yellow solid.

Example 24: Synthesis of Compound 160273

Compound 160210: A mixture of3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (95mg, 0.37 mmol), K₂CO₃ (101 mg, 0.73 mmol) and tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodanylethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Themixture was quenched with water and extracted with DCM (200 mL). Theorganic layer was dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM:MeOH=20:1, Rf=0.48) to give tert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(83 mg, 0.09 mmol, 36% yield) as a pale-yellow solid.

Compound 160273: To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate(83 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.13 mL, 1.74 mmol) andstirred at room temperature for 7 h. The mixture was poured into icedwater and neutralized with sat. NaHCO₃ solution to pH 8. The residue wastaken up in DCM (20 mL) and water (10 mL). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄ and concentratedto dryness to give3-[6-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(73 mg, 0.08 mmol, 92% yield) as a yellow solid.

Example 25: Synthesis of Compound 160570

Compound 160491: To a solution of2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol(0.43 g, 1.24 mmol) in dry DMF (4 mL) was added NaH (0.10 g, 2.48 mmol)at 0° C. and stirred at room temperature for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(1.54 g, 3.72 mmol) in dry DMF (4 mL) was added to the reaction mixtureand stirred at the same temperature for 14 h. The mixture was cooled to0° C., quenched with water (30 mL) and extracted with DCM (30 mL) wasadded. The organic layer was washed with water (30 mL) and brine (30mL), dried over anhydrous Na₂SO₄, concentrated and purified by columnchromatography (EtOAc:DCM=1:5, Rf=0.33) to give2-[2-[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl4-methylbenzenesulfonate (234 mg, 0.40 mmol, 32% yield) as an orangesolid.

Compound 160508: A mixture of2-[2-[[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]-3,8a-dihydroimidazo[1,2-a]pyridin-6-yl]oxy]ethoxy]ethyl4-methylbenzenesulfonate (232 mg, 0.39 mmol) and NaI (70 mg, 0.47 mmol)in ACN (2 mL) was heated at 80° C. for 14 h. The mixture was added waterand extracted with DCM. The organic layer was washed with water (20 mL)and brine (20 mL), dried over Na₂SO₄, concentrated and purified bychromatography (EtOAc:DCM=1:10, Rf=0.20) to give6-fluoranyl-5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine(204 mg, 0.37 mmol, 95% yield) as a pale-yellow solid.

Compound 160570: A mixture of2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione(101 mg, 0.37 mmol), Cs₂CO₃ (180 mg, 0.55 mmol) and6-fluoranyl-5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine(101 mg, 0.18 mmol) in DMF (3 mL) was heated at 50° C. for 4 h and thenstirred at room temperature for 3 days. The mixture was triturated withwater and the resulting precipitate was collected and purified by columnchromatography (EtOAc:DCM=1:4, Rf=0.05) to give2-[1-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl]-2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione(15 mg, 0.02 mmol, 11% yield) as a brown solid.

Example 26: Synthesis of Compound 160703

Compound 160686: A mixture of2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione(68 mg, 0.25 mmol), Cs₂CO₃ (121 mg, 0.37 mmol) and tert-butylN-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (80 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C.for 3 h. The mixture was diluted with DCM, extracted with water, driedover MgSO₄, concentrated and purified by column chromatography on NHsilica gel (MeOH:DCM=1:20, Rf=0.2) to give tert-butylN-[2-[2-[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(25 mg, 0.03 mmol, 25% yield) as a yellow solid.

Compound 160703: To a solution of tert-butylN-[2-[2-[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate(42 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.04 mL, 0.53 mmol) at0° C. and stirred at room temperature for 23 h. The mixture wasneutralized with sat. NaHCO₃ solution to pH 8 and extracted with DCM.The organic layer was dried over Na₂SO₄ and concentrated to dryness togive2-[1-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethyl]-2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione(34 mg, 0.05 mmol, 88% yield) as a yellow solid.

Example 27: Synthesis of Compound 161262

Compound 161176: To a solution of tert-butyl2-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate(250 mg, 0.51 mmol) in DMF (5 mL) was cooled to 0° C., added NaH (37 mg,0.92 mmol) and stirred at the same temperature for 30 min. Dimethyl4-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]benzene-1,2-dicarboxylate(302 mg, 0.67 mmol) was added to the reaction mixture and stirred atroom temperature for 20 h and heated to 50° C. for 20 h. The mixture wasquenched with water and extracted with DCM. The organic layer was washedwith brine, dried over MgSO₄, concentrated and purified by columnchromatography on silica gel (EtOAc:DCM=1:2.3, Rf=0.375) to afforddimethyl4-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate(183 mg, 0.24 mmol, 46% yield) as a yellow oil.

Compound 161217: To a solution of dimethyl4-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate(273 mg, 0.36 mmol) in EtOH (3 mL) was added NaOH (228 mg, 5.70 mmol) inwater (3 mL) and stirred at room temperature for 4 days. The reactionwas neutralized with 1N HCl solution to pH 1. The resulting precipitatewas collected, washed with water (10 mL) and dried over vacuo to give4-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalicacid (201 mg, 0.31 mmol, 88% yield) as a white solid.

Compound 161230: A mixture of4-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalicacid (201 mg, 0.31 mmol) and 3-azanylpiperidine-2,6-dione hydrochloride(78 mg, 0.47 mmol) in pyridine (3 mL) was heated at 120° C. for 19 h.The solvent was removed by vacuum and the resulting residue wastriturated with water. The precipitate was collected and purified bycolumn chromatography on NH silica gel (MeOH:DCM=3:100, Rf=0.25) to givetert-butyl2-[4-[6-[2-[2-[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate(47 mg, 0.06 mmol, 20% yield) as a yellow solid.

Compound 161262: A solution of tert-butyl2-[4-[6-[2-[2-[2-[2,6-bis(oxidanyldene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate(47 mg, 0.06 mmol) in DCM (3 mL) was added TFA (0.07 mL, 0.96 mmol) andstirred at room temperature for 23 h. The mixture was neutralized withsat. NaHCO₃ solution to pH 8. The resulting precipitate was collected,washed with water and dried over vacuum to give2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione(36 mg, 0.05 mmol, 82% yield) as a yellow solid.

Example 28: Synthesis of Compound 164625

Compound 164581: A mixture of tert-butyl3-[2-(2-iodanylethoxy)ethoxy]propanoate (500 mg, 1.45 mmol), K₂CO₃ (602mg, 4.36 mmol) and methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate(467 mg, 1.60 mmol) in DMF (15 mL) was heated at 80° C. for 7 h. Themixture was diluted with EtOAc, extracted with brine, dried over MgSO₄,concentrated and purified by column chromatography (MeOH:DCM=1:20,Rf=0.48) to give tert-butyl3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoate(387 mg, 0.81 mmol, 56% yield) as a white solid.

Compound 164617: To a solution of tert-butyl3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoate(387 mg, 0.81 mmol) in DCM (10 mL) was added TFA (0.62 mL, 8.12 mmol)and stirred at room temperature for 15 h. The mixture was concentratedto dryness to give3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoicacid TFA salt (494 mg, 1.18 mmol) as a white oil.

Compound 164625: A mixture of3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoicacid (346 mg, 0.82 mmol), TBTU (352 mg, 1.10 mmol) and2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-amine(190 mg, 0.55 mmol) in pyridine (3 mL) was stirred at room temperaturefor 17 h. The mixture was added with water and the resulting precipitatewas collected by filtration and purified by column chromatography(MeOH:DCM=1:19, Rf=0.3) to give3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]propanamide(285 mg, 0.36 mmol, 66% yield) as a yellow solid.

Example 29: Synthesis of Compound 164657

Compound 164263: A mixture of tert-butylN-(2-bromanyl-1,3-benzothiazol-6-yl)carbamate (1100 mg, 3.34 mmol),N,N-dimethyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]pyridin-2-amine(1704 mg, 4.34 mmol), Pd(dppf)Cl₂ (247 mg, 0.33 mmol) and 2M Na₂CO₃(aq)solution (5 mL, 10.02 mmol) in dioxane (35 mL) was heated at 80° C. for16 h under argon. The mixture was filtered through a Celite pad and theresidue was taken up in EtOAc (100 mL) and water (50 mL). The organiclayer was washed with water (50 mL), brine (50 mL), dried over Na₂SO₄and concentrated to dryness. The residue was purified by columnchromatography (EtOAc:Hex=1:4, Rf=0.15) to give tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(1.06 g, 2.05 mmol, 61% yield) as a yellow oil.

Compound 164346: To a solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(1056 mg, 2.05 mmol) in DMF (20 mL) was added NaH (148 mg, 6.16 mmol) at0° C. and stirred at 25° C. for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(2.55 g, 6.16 mmol) in DMF (20 mL) was added to the reaction mixture andstirred at room temperature for 14 h. The mixture was quenched withwater at 0° C. The residue was taken up in EtOAc (50 mL) and water (50mL). The organic layer was washed with water (50 mL), brine (50 mL),dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (955 mg, 1.26 mmol, 61% yield) as a yellow oil.

Compound 164398: A mixture of2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (955 mg, 1.26 mmol), NaI (378 mg, 2.52 mmol) inMeCN (20 mL) was heated at 80° C. for 17 h. The residue was taken up inEtOAc (50 mL) and water (50 mL). The organic layer was washed with water(50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by column chromatography (EtOAc:Hex=1:1, Rf=0.7) to givetert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate(805 mg, 1.13 mmol, 90% yield) as a yellow oil.

Compound 164350: A mixture of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate(110 mg, 0.15 mmol), K₂CO₃ (64 mg, 0.46 mmol), and methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (50 mg, 0.17 mmol) in DMF (2.5 mL) was heated at80° C. for 8 h. The mixture was added water, extracted with DCM, driedover MgSO₄ and concentrated to dryness. The residue was purified bycolumn chromatography (MeOH:DCM=1:20, Rf=0.4) to give tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(110 mg, 0.13 mmol, 84% yield) as a yellow solid.

Compound 164657: To a solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(550 mg, 0.65 mmol) in DCM (10 mL) was added TFA (0.75 mL, 9.76 mmol) at25° C. and stirred for 15 h. The mixture was poured into ice water andneutralized with sat. NaHCO₃ solution to pH 8. The residue was taken upin DCM (20 mL) and water (10 mL). The organic layer was washed withwater (10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by column chromatography(DCM:MeOH=10:1, Rf=0.58) to give3-[6-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (254 mg, 0.34 mmol, 52% yield) as a yellow solid.

Example 30: Synthesis of Compound 162640

Compound 162534: A solution of tert-butylN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate(1.52 g, 4.75 mmol), 2-(4-bromophenyl)-6-methoxy-imidazo[1,2-a]pyridine(1.2 g, 3.96 mmol), and triphenylphosphine (34.6 mg, 0.13 mmol) in EtOH(4 mL) and toluene (2.8 mL) was purged with argon and then added withK₂CO₃ solution (1.75M, 7.92 mL, 13.85 mmol) dropwise. The mixture wasadded with Pd(OAc)₂ (87 mg, 0.40 mmol) under argon and heated at 90° C.for 4 h. The mixture was filtered through celite pad, poured intosaturated NaHCO₃ solution, and extracted with EtOAc. The organic layerwas dried over MgSO₄, concentrated and purified by column chromatography(EtOAc:DCM=1:4, Rf=0.3) to give tert-butylN-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(987 mg, 2.37 mmol, 60% yield) as a pale-brown solid.

Compound 162547: A solution of2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(2.86 g, 6.90 mmol) in DMF (10 mL) was added NaH (368 mg, 9.20 mmol) at0° C. and stirred at room temperature for 1 h. The mixture was addedwith 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl4-methylbenzenesulfonate (2.86 g, 6.90 mmol) in DMF (10 mL) and stirredat room temperature for 19 h. The mixture was cooled to 0° C., quenchedby adding water and diluted with DCM. The resulting mixture was washedwith water and brine, dried over Na₂SO₄, concentrated and purified bycolumn chromatography (EtOAc:DCM=4:1, Rf=0.4) to give2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (924 mg, 1.40 mmol, 61% yield) as an orangeoil.

Compound 162568: A mixture of2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (924 mg, 1.40 mmol) and NaI (421 mg, 2.81 mmol)in CH₃CN (20 mL) was heated at 80° C. for 17 h. The mixture was dilutedwith DCM, washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, concentrated and purified by column chromatography(MeOH:DCM=1:100, Rf=0.19) to give tert-butylN-[2-(2-iodanylethoxy)ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(585 mg, 0.95 mmol, 68% yield) as an orange solid.

Compound 162599: A solution of tert-butylN-[2-(2-iodanylethoxy)ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(250 mg, 0.41 mmol),3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (212mg, 0.81 mmol) and K₂CO₃ (169 mg, 1.22 mmol) in DMF (4 mL) was heated at50° C. for 3 h. The mixture was quenched with water and the resultingsolid was collected by filtration. The solid was washed with water andthe residue was purified by NH gel column chromatography (MeOH:DCM=3:100, Rf=0.33) to give tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(76 mg, 0.10 mmol, 25% yield) as a white solid.

Compound 162640: To a solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(76 mg, 0.10 mmol) in DCM (2 mL) was added TFA (0.12 mL, 1.53 mmol) andstirred for 38 h. The mixture was poured into iced water and neutralizedwith sat. NaHCO₃ solution to pH 8. The residue was taken up in DCM (20mL) and water (10 mL). The organic layer was washed with water (10 mL),brine (10 mL), dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM:MeOH=100:3, Rf=0.35) to give3-[6-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(22 mg, 0.03 mmol, 33% yield) as a pale-brown solid.

Example 31: Synthesis of Compound 162843

Compound 162723: To a solution of2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(4.72 g, 11.38 mmol) in DMF (30 mL) was added NaH (455 mg, 11.38 mmol)at 0° C. and stirred at room temperature for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(4.72 g, 11.38 mmol) in DMF (30 mL) was added to the reaction mixtureand stirred at room temperature for another 16 h. The mixture was cooledto 0° C. and quenched with water. The mixture was diluted with DCM,washed with water and brine, dried over Na₂SO₄, concentrated andpurified by column chromatography (EtOAc:Hex=1:1, Rf=0.23) to give2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (1.3 g, 1.97 mmol, 69% yield) as an orangesolid.

Compound 162762: A mixture of2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (1.3 g, 1.97 mmol) and NaI (592 mg, 3.95 mmol)in ACN (10 mL) was heated at 80° C. for 15 h. The mixture was addedwater and extracted with DCM. The organic layer was washed with water(50 mL), brine (50 mL), dried over Na₂SO₄, concentrated to dryness andpurified by chromatography (MeOH:DCM=1:100, Rf=0.19) to give tert-butylN-[2-(2-iodanylethoxy)ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(920 mg, 1.50 mmol, 76% yield) as a yellow solid.

Compound 162798: A mixture of tert-butylN-[2-(2-iodanylethoxy)ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(200 mg, 0.33 mmol),3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (169mg, 0.65 mmol) and Na₂CO₃ (103 mg, 0.98 mmol) in DMF (4 mL) was heatedat 50° C. for 37 h. The mixture was added with water and the resultingprecipitate was collected by filtration, washed with water and purifiedby column chromatography on NH gel (MeOH:DCM=1:100, Rf=0.21) to givetert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(68 mg, 0.09 mmol, 28% yield) as a yellow solid.

Compound 162843: To a solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.07 mL, 0.9100 mmol)and stirred at room temperature for 48 h. The mixture was diluted withDCM (3 mL) and neutralized with sat. NaHCO₃(aq.) solution to pH 8. Theprecipitate was collected and washed with DCM to give3-[6-[2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(38 mg, 0.05 mmol, 59% yield) as a yellow solid.

Example 32: Synthesis of Compound 165559

Compound 165511: A solution of2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(2567 mg, 6.19 mmol) in DMF (10 mL) was cooled to 0° C., added NaH (248mg, 6.19 mmol) and then stirred at room temperature for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(2567 mg, 6.19 mmol) was added to the reaction mixture and stirred atroom temperature for 17 h. The reaction was cooled to 0° C. and quenchedby adding water. The mixture was diluted with DCM, washed with water andbrine, dried over Na₂SO₄, concentrated and purified by columnchromatography (DCM:EtOAc=10:1, Rf=0.3) to give2-[2-[[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (455 mg, 0.68mmol, 33% yield) as a white solid.

Compound 165547: A mixture of methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate(220 mg, 0.75 mmol), K₂CO₃ (284 mg, 2.06 mmol), KI (11 mg, 0.07 mmol)and2-[2-[[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (455 mg, 0.69 mmol) in DMF (6 mL) was heated at80° C. for 7 h. The mixture was diluted with EtOAc (20 mL), extractedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄, concentratedand purified by column chromatography (MeOH:DCM=1:20 , Rf=0.4) to givetert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]carbamate(245 mg, 0.33 mmol, 48% yield) as white solid.

Compound 165559: A solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]carbamate(245 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.38 mL, 4.89 mmol) andstirred at room temperature for 20 h. The mixture was diluted with DCM(20 mL) and neutralized with sat. NaHCO₃ solution to pH 8. The mixtureextracted with water, dried over MgSO₄, concentrated and purified bycolumn chromatography (DCM:MeOH=20:1, Rf=0.3) to give3-[6-[2-[2-[[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(160 mg, 0.24 mmol, 75% yield) as a white solid.

Example 33: Synthesis of Compound 163685

Compound 162862: To a solution of2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-ol(516 mg, 1.24 mmol) in dry DMF (12 mL) was added NaH (149 mg, 3.72 mmol)at 0° C. and stirred at room temperature for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(1543 mg, 3.72 mmol) in dry DMF (12 mL) was added to the reactionmixture and stirred at the same temperature for 18 h. The mixture waspoured into water (50 mL) and extracted with DCM (50 mL). The organiclayer was washed with water (50 mL) and brine (50 mL), dried overanhydrous Na₂SO₄, concentrated and purified by column chromatography(Rf=0.51, EtOAc:DCM=1:9) to give2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethyl4-methylbenzenesulfonate (627 mg, 0.95 mmol, 77% yield) as a pale yellowsolid.

Compound 162891: A mixture of2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethyl4-methylbenzenesulfonate (627 mg, 0.95 mmol) and NaI (286 mg, 1.91 mmol)in ACN (10 mL) was heated at 80° C. for 17 h. The mixture was addedwater (20 mL) and extracted with EtOAc. The organic layer was washedwith brine, dried over MgSO₄ and concentrated to dryness to give5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-pyridin-2-amine(540 mg, 0.88 mmol, 92% yield) as a yellow solid.

Compound 163685: A mixture of5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-pyridin-2-amine(100 mg, 0.16 mmol),3-(7-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (85mg, 0.33 mmol) and K₂CO₃ (68 mg, 0.49 mmol) in DMF (5 mL) was heated at50° C. for 18 h. The mixture was added water and extracted with DCM. Theorganic layer was washed with brine, dried over MgSO₄, concentrated andpurified by column chromatography (MeOH:DCM=1:20, Rf=0.45) to give3-[7-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(33 mg, 0.04 mmol, 25% yield) as a yellow solid.

Example 34: Synthesis of Compound 163863

Compound 163863: A mixture of2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-ol (166mg, 0.48 mmol),3-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]propanoicacid (90 mg, 0.24 mmol), DMAP (3 mg, 0.02 mmol) and DCC (52 mg, 0.25mmol) in pyridine (2 mL) was stirred at room temperature for 15 h. Thesolvent was removed by reduced pressure. The residue was redissolved inDCM (10 mL), washed with water (5 mL) and brine (5 mL), dried overMgSO₄, concentrated and purified by column chromatography(MeOH:DCM=5:100, Rf=0.14) to give[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]3-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]propanoate(14 mg, 0.02 mmol, 8% yield) as a yellow solid,

Example 35: Synthesis of Compound 164484

Compound 164431: A solution of tert-butylN-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(400 mg, 0.96 mmol) in dry DMF (10 mL) was cooled to 0° C. and added NaH(115 mg, 2.88 mmol). The resulting mixture was stirred at roomtemperature for 1 h.2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethyl4-methylbenzenesulfonate (1321 mg, 2.88 mmol) in dry DMF (10 mL) wasadded to the reaction mixture and stirred at the same temperature for 17h. The mixture was quenched with water (30 mL) and extracted with DCM(30 mL). The organic layer was washed with brine (30 mL), dried overanhydrous Na₂SO₄, concentrated and purified by column chromatography(EtOAc:DCM=1:4, Rf=0.4) to give2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (350 mg, 0.50 mmol, 52% yield) as a yellowsolid.

Compound 164438: A mixture of2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (350 mg, 0.50 mmol) and NaI (149 mg, 1.00 mmol)in ACN (10 mL) was heated at 80° C. for 6 h. The mixture was added waterand extracted with DCM. The organic layer was washed with water (50 mL)and brine (50 mL), dried over Na2SO4 and concentrated to dryness to givetert-butylN-[2-[2-(2-iodanylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(317 mg, 0.48 mmol, 97% yield) as a yellow solid.

Compound 164465: A mixture of tert-butylN-[2-[2-(2-iodanylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(100 mg, 0.15 mmol), K₂CO₃ (63 mg, 0.46 mmol) and methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate(49 mg, 0.17 mmol) in DMF (5 mL) was heated at 80° C. for 6 h. Themixture was added water and extracted with DCM. The organic layer wasdried over MgSO₄, concentrated and purified by column chromatography(MeOH:DCM=3:100, Rf=0.3) to give tert-butylN-[2-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(63 mg, 0.08 mmol, 52% yield) as a white solid.

Compound 164484: To a solution of tert-butylN-[2-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate(63 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.09 mL, 1.19 mmol) andstirred at room temperature for 14 h. The mixture was poured into icedwater and neutralized with sat. NaHCO₃ solution to pH 8. The mixture wasdiluted with DCM (20 mL) and extracted with water (10 mL) and brine (10mL), dried over Na2SO4 and concentrated to dryness to give3-[6-[2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(52 mg, 0.07 mmol, 89% yield) as a pale-brown solid.

Example 36: Synthesis of Compound 165013

Compound 164953: To a solution of tert-butylN-methyl-N-[5-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]pyridin-2-yl]carbamate(200 mg, 0.33 mmol) in dry DMF (5 mL) was added NaH (40 mg, 1.00 mmol)at 0° C. and stirred at room temperature for 1 h.2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate(414 mg, 1.00 mmol) in dry DMF (5 mL) was added to the reaction mixtureand stirred at the same temperature for 14 h. The mixture was quenchedwith water (30 mL) and extracted with DCM (30 mL). The organic layer waswashed with water (30 mL) and brine (30 mL), dried over anhydrousNa₂SO₄, concentrated and purified by column chromatography(EtOAc:DCM=1:9, Rf=0.4) to give2-[2-[[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (130 mg, 0.15 mmol, 46% yield) as a yellowsolid.

Compound 164984: A mixture of methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate(50 mg, 0.17 mmol), K₂CO₃ (64 mg, 0.46 mmol), KI (2.56 mg, 0.02 mmol)and2-[2-[[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl4-methylbenzenesulfonate (130 mg, 0.15 mmol) in DMF (5 mL) was heated at80° C. for 6 h. The mixture was diluted with DCM (5 mL), cooled to 0° C.and added water (5 mL) dropwise. The mixture was extracted with water(10 mL) and brine (10 mL), dried over Na₂SO₄, concentrated and purifiedby column chromatography (MeOH:DCM=3:100 , Rf=0.3) to give tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(79 mg, 0.08 mmol, 55% yield) as colorless oil.

Compound 165013: To a solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(79 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.1 mL, 1.27 mmol) andstirred at room temperature for 14 h. The mixture was poured into icewater and neutralized with sat. NaHCO₃ solution to pH 8. The mixture wasdiluted with DCM (20 mL) and extracted with water (10 mL) and brine (10mL). The organic layer was collected, dried over Na₂SO₄, concentratedand purified by column chromatography on silica gel (MeOH:DCM=3:100,Rf=0.2) to give3-[6-[2-[2-[[2-[4-[6-(methylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(29 mg, 0.04 mmol, 45% yield) as a yellow solid.

Example 37: Synthesis of Compound 166288

Compound 166191: A solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(447 mg, 0.87 mmol) in DMF (8 mL) was added NaH (63 mg, 2.61 mmol) at 0°C., stirred at room temperature for 1 h and then added5-(4-methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1075 mg,2.61 mmol) in DMF (8 mL). The resulting mixture was stirred at roomtemperature for another 16 h, cooled to 0° C. and quenched by addingwater. The residue was taken up in DCM (50 mL) and water (50 mL). Theorganic layer was washed with water (50 mL), brine (50 mL), dried overNa₂SO₄, and purified by column chromatography on silica gel(DCM:EtOAc=9:1, Rf=0.52) to give5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl4-methylbenzenesulfonate (515 mg, 0.68 mmol, 79% yield) as a yellowsolid.

Compound 166226: A mixture of5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl4-methylbenzenesulfonate (514 mg, 0.68 mmol), K₂CO₃ (282 mg, 2.04 mmol),KI (11 mg, 0.07 mmol) and methyl5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate(219 mg, 0.75 mmol) in DMF (8 mL) was stirred at room temperature for 22h and then heated to 80° C. for 6 h. The mixture was diluted with DCM (5mL), cooled to 0° C. and added water (5 mL) dropwise. The mixture waswashed with water (10 mL) and brine (10 mL), dried over Na₂SO₄,concentrated and purified by column chromatography on silica gel(MeOH:DCM=1:20 , Rf=0.55) to give tert-butylN-[5-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(205 mg, 0.24 mmol, 36% yield) as yellow solid.

Compound 166288: To a solution of tert-butylN-[5-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(205 mg, 0.24 mmol) in DCM (3 mL) was added TFA (0.28 mL, 3.65 mmol) andstirred at room temperature for 16 h. The mixture was poured into icedwater and neutralized with sat. NaHCO3 solution to pH 8. The residue wastaken up in DCM (20 mL) and water (10 mL). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄ and concentratedto dryness to give3-[6-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]pentoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione(132 mg, 0.17 mmol, 71% yield) as a yellow solid.

Example 38: Synthesis of Compound 166399

Compound 166196: A solution of tert-butylN-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(300 mg, 0.58 mmol) in DMF (5 mL) was cooled to 0° C. and added NaH (56mg, 2.33 mmol). The mixture was stirred at room temperature for 1 h,added 2-azidoethyl 4-methylbenzenesulfonate (281 mg, 1.17 mmol) in DMF(5 mL) and heated at 50° C. for 20 h. The mixture was cooled to 0° C.and added water (5 mL). The resulting precipitation was collected byfiltration, washed with water and dried over vacuum. The residue waspurified by column chromatography on silica gel (EtOAc:DCM=1:20, Rf=0.6)to give tert-butylN-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(320 mg, 0.55 mmol, 94% yield) as a yellow solid.

Compound 166264: A solution of tert-butylN-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(341 mg, 0.58 mmol) in THF (5 mL)/EtOH (5 mL) was added Pd(OH)₂ (1701mg, 1.61 mmol) and stirred under 1 atmosphere of H2 for 4 h. The mixturewas filtered through a Celite pad and the filtrate was concentrated todryness. The residue was purified by column chromatography(DCM:EtOAc=20:1, Rf=0.15) to give tert-butylN-(2-azanylethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(226 mg, 0.41 mmol, 69% yield) as pale-yellow solid.

Compound 166306: A mixture of tert-butylN-(2-azanylethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(326 mg, 0.59 mmol),2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethanoicacid (372 mg, 1.17 mmol), EDC (280 mg, 1.46 mmol) and HOBt (198 mg, 1.46mmol) in pyridine (6 mL) was stirred at room temperature for 16 h. Thesolvent was removed by vacuum and the resulting residue was redissolvedin EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL). Theorganic layer was dried over Na₂SO₄, concentrated and purified by columnchromatography on silica gel (MeOH:DCM=1:20, Rf=0.3) to give tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethanoylamino]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(277 mg, 0.32 mmol, 55% yield) as a yellow solid.

Compound 166399: A solution of tert-butylN-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethanoylamino]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate(277 mg, 0.32 mmol) in DCM (3 mL) was added TFA (0.37 mL, 4.85 mmol) andstirred at room temperature for 23 h. The mixture was poured into icedwater and neutralized with sat. NaHCO3 solution to pH 8. The residue wastaken up in DCM (20 mL) and water (10 mL). The organic layer was washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄ and concentratedto give2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]-N-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethyl]ethanamide(239 mg, 0.30 mmol, 93% yield) as a yellow solid.

Example 39: In Vitro Fluorescence-Based Recombinant Tau Binding Assay

(A) Expression and purification of human Tau: 1 mM IPTG (Sangon Biotech,Cat. No A100487) was used to induce production of tau by bacteria (BL₂₁,Invitrogen, Cat. No C600003) transformed with a full-length 2N₄R tauexpression plasmid. After 3 hours, cell pellet was resuspended in lysisbuffer (100 mM PIPES, 1 mM EGTA, 1 mM MgSO₄, pH 6.8) and lysed bysonication followed by centrifugation (15,000 rpm, 15 min, 4° C.). Thesupernatant was then placed in a boiling water bath for 20 min, followedby centrifugation (15,000 rpm, 15 min, 4° C.). Supernatant was loadedonto a Q-Sepharose® Fast Flow column (GE healthcare, Cat. No17-0510-01), the flow-through fraction was loaded onto an SP-Sepharose®Fast Flow column (GE healthcare, Cat. No 17-0729-01), and tau proteinwas eluted with elution buffer (100 mM PIPES, 1 M NaCl, 1 mM EGTA, 1 mMMgSO₄, 0.2 M NaCl, pH 6.8). Collected fractions of tau-containingeluates were pooled, concentrated and dialyzed against HEPES buffer (25mM HEPES, 0.1 mM EDTA, 0.5 mM DTT, 100 mM NaCl, pH 7.2) and stored at−80° C. in small aliquots until use. Protein concentration wasdetermined by UV absorption.

(B) Preparation of heparin-induced aggregated tau (aTau): 2 μM of tauprepared in 30 mM Tris-HCl, pH 7.5 buffer was incubated in tube with 15μM heparin (Sigma, Cat. No H3149) at 37° C. for 24 hours.

(C) Compound fluorescent spectra scanning assay: Compounds weredissolved in 100% DMSO, and 40 nM aTau was incubated with 10 μM of eachcompound in 2% DMSO in 96 well plate (Corning, Cat. No 3573) at 37° C.for 1 hour. Emission and excitation of the compound was scanned bymicroplate spectrometer (EnSpire 2300, PerkinElmer).

(D) In vitro fluorometric aTau binding assays: 2 μM aTau was diluted to0.04 μM with 30 mM Tris-HCl (pH 6.8), and then incubated with seriallydiluted compound (three-fold serial dilutions, from 10 to 0.00017 μM) ina 96-well plate (Corning, Cat. No 3573) at 37° C. for 1 hour.Fluorescence intensity (excitation/emission=370/500 nm) of APN-0729 wasread by microplate spectrometer (EnSpire 2300, PerkinElmer). Compound Kdvalues were calculated using the following equation: Y=B_(max)* X(Kd+X), where X is the concentration of compound; Y is the fluorescencesignal of (compound+aTau)−(compound+DMSO); and B_(max) is the maximumsignal. The results are shown in Table 2 below.

TABLE 2 Competition Assay with PBB5 Compound Ex/Em (nm) Kd (μM) PBB5(μM) Bmax (%) 159985 375/485 0.10 0.32 71 160219 375/480 0.11 0.15 69160273 375/495 0.47 0.27 59 160313 370/500 0.08 0.22 64 160275 375/5050.23 1.29 96 160703 390/500 0.10 1.00 =100 160383 375/525 0.55 0.27 80160624 380/500 0.12 0.55 =100 160744 355/405 0.15 5.96 113 160570350/520 0.36 2.26 =100 160371 300/400 0.29 >10 =100.0

(E) PBBS competition assay: 2 μM of aTau was diluted to 0.12 μM by withmM Tris-HCl (pH 6.8) and then incubated with 0.1 μM2-(4-(2-(methylamino)pyridine-5-yl)-1,3-butadiene-1-yl)benzothiazole-6-ol(PBB5) and serially diluted compound (three-fold serial dilution, from10 to 0.00017 μM) in a 96-well plate (Corning, Cat. No 3573) at 37° C.for 1 hour. Fluorescence intensity (excitation/emission=530/690 nm) ofPBB5 was read by microplate spectrometer (EnSpire 2300, PerkinElmer).Percentage of competition was calculated using the following equation:(Max−well of compound alone)/(Max−Min)*100%, where Max=(Tau+PBB5)signals−(buffer+PBB5) signals; and Min=(buffer+PBB5)signals−(buffer+PBB5) signals.

The IC₅₀ value of each compound was calculated with GraphPad Prismsoftware using the “4 Parameter Logistic Model or SigmoidalDose-Response Model”:

Y=Bottom+(Top−Bottom)/(1+(IC50/×)^HillSlope)

To examine tau binding ability of the compounds, we performedfluorescence-based in vitro tau binding assay. All compounds retainedtau binding ability as well as competitive nature with PBB5.

Example 40: Cell-Based Tau Binding Assay

(A) Mouse brain lysate preparation as the source of tau seeds: Threemonths old WT and rTg4510 mouse were sacrificed by cervical dislocation.The brains were quickly removed from the skulls, weighed, thecerebellums discarded, and the remaining brains dissected along themidline on ice. Half of each cerebrum was placed into a homogenizationtube (MP Biomedicals) and kept on ice. Ice-cold homogenization bufferwas added, 5-fold volumes to brain weight. The homogenate was vortexedby FastPrep-24™ 5G (MP biomedicals) for 40 second in 6 m/s rate, andthen centrifuged (Eppendorf) at 13,000×g for 15 min at 4° C. Thesupernatant of brain lysate was transferred into a new microfuge tubeand stored at -80° C.

Because the homogenization buffer caused minor toxicity to HEK cells,the brain lysate underwent a buffer exchange from Tris-based buffer toPBS. The brain lysate was thawed on ice. Sterile PBS was added into a2-ml centrifugal filter tube (10K cut-off, Amicon), and then centrifugedat 4500×g for 2 min at 4° C. to rinse the tube. The thawed lysate wasadded into the filter tube, and filled with sterile 1×PBS to 2 mL. Thetube was centrifuged at 4500×g for 60 min at 4° C. The PBS wash step wasrepeated. After the centrifugation step, 300 μL of supernatant in thebottom of centrifuged tube was collected and kept on ice. The rest ofthe supernatant was repeated to fill the buffer and centrifuged for 20min again. The second collected supernatant was combined with theprevious one. The protein concentration was measured by Bradford assay(Bio-Red). The mouse brain lysate exchanged buffer was diluted withsterile 1× PBS to 3 mg/mL, aliquoted to 90 and 180 μL in microfuge tubesand stored at −80° C.

(B) Cell culture: Tau RD(LM)-eGFP HEK293 cells were cultured in twokinds of culture media. For cell maintenance, the cells were cultured inDMEM/F-12 (Gibco) supplemented with 10% FBS (Gibco), 1% PS (Gibco) and 6μg/mL puromycin (Gibco) and plated by 1×10⁶ cells/well in 6 well plate(Greiner). Cells were sub-cultured twice per week. For tau bindingtests, the cells were cultured in DMEM/F-12 supplemented with 1.25% FBS,1% PS and 6 μg/mL puromycin (binding medium) and plated by 1.5×10⁴cells/well in a 96 well plate pre-coated with poly-D-lysine (BDBiosciences).

(C) Compound Treatment: Frozen mouse brain lysate was thawed on ice anddiluted to 1 μg/μL with 1× PBS. Diluted brain lysate or 1×PBS were addedinto each well of a 96-well plate containing cells cultured for 24 hrs.After 24 hours of incubation, the culture medium was replaced with freshbinding medium. On the third day after tau seeding, 10 mM of thecompound stock solution were serially diluted two folds down from 1000,500, 250, 125, 62.5, 31.25, 15.63, 7.8 nM in fresh binding medium andthe DMSO (Sigma) concentration was maintained at 0.1% for all wells. Themedia in the 96-well plate were then replaced with the medium containingvarious concentrations of the compound. The plate was placed back to theincubator for 2 hours, and medium was replaced with binding mediumcontaining 8% NucRed 647 (Thermo Fisher) to stain the nucleus for 30minutes. The cells were fixed with 4% PFA (Electron Microscopy Sciences)for 20 minutes at RT then changed to 1× PBS for image acquisition.

(D) Image acquisition and analysis: All images were taken by ImageXpressMicro Confocal (Molecular devices) using a 20× objective lens, andexcitation/emission settings were defined by the DAPI, FITC20 & Cy5channels for APN-0729, Tau-eGFP & Nucleus, respectively. All images wereprocessed for tau binding analysis using a customized module ofMetaXpress software (Molecular devices). The module is capable ofmeasuring: (1) total cell numbers (=nuclei numbers); (2) tau aggregatenumbers; (3) tau positive cell numbers; (4) tau aggregate average area;(5) tau and compound double-positive aggregate numbers; (6) tau andcompound double-positive cell numbers; (7) compound average intensity intau aggregates; (8) tau and compound double-positive area in tauaggregates.

Example 41: Tau Degradation Assay

(A). Cell-based model of Tau inclusion formation: Six month old rTg4510mouse brain lysates were used as the source of tau seeds, prepared asdescribed in Example 26 above. P301L-Tau-FL-GFP HEK293 cells representHEK293 cells express full-length human tau T40 (2N4R) carrying the P301Lmutation with a GFP tag (P301L-Tau-FL-GFP). 1×10⁶ of P301L-Tau-FL-GFPHEK293 cells were cultured on a 6-well plate in culture mediumcontaining DMEM/F-12 (Gibco) supplemented with 10% fetal bovine serum(FBS) (Gibco), 1% Penicillin-Streptomycin (Gibco) and 0.5 mg/mlgeneticin (Thermo Fisher Scientific) for 24 hours to reach 70-90%confluency, indicating the cells were ready for transfection. 50 μg of6-month-old rTg4510 mouse brain lysate was diluted in 400 μL of serumfree medium and mixed with 16 μL of lipofectamine 3000 reagent (ThermoFisher Scientific) diluted in 400 μl of serum free medium. A solutionmixture of rTg4510 brain lysate and lipofectamine 3000 was incubated atroom temperature for 25 min. The culture media were removed, and then asolution mixture of rTg4510 lysate and lipofectamine 3000 was added tothe cells for transfection. The solution mixture was incubated at roomtemperature for five hours, followed by medium change to 10% fetalbovine serum (FBS). After two-day incubation, Tau aggregates (Tau spots)were induced and images were acquired by ImageXpress Micro Confocalhigh-content imaging system (Molecular Devices) as described in Example52 above. Analysis was performed by two customized modules in MetaXpresssoftware (Molecular Devices) for aggregated tau analysis. Outputincluded cell numbers, numbers of tau spots, average intensity of tauspots, and average size of tau spots.

(B). Compound treatment: 100 μL of 3×10⁴ cells comprising Tauaggregates, prepared as described above in step (A), were plated on a96-well plate coated with poly-D-lysine (BD Biosciences) and culturedfor 24 hours. Compounds to be tested were dissolved in culture mediumcontaining 0.1% DMSO. Each of test compounds in the concentration of 1,0.2 and 0.04 μM was added to the cells comprising Tau aggregates andincubated at 37° C. for 24 hours. After that, culture medium wasremoved, cells were washed with PBS solution and then lysed using 30 μLof lysis buffer (PBS containing 0.3% Triton X-100 and 400 mM NaCl) forone hour at 4° C., and then cell lysate was diluted by 170 μl of PBScontaining 400 mM NaCl. Cell lysate was filtrated by a 0.45 μMfiltration plate (Pall) and applied for Tau aggregation assay.

(C). Control cell lysate: control cell lysate was collected fromnon-seeded cells.

(D). ELISA-based Tau aggregation assay: APNmAb005 ELISA kit for Tauaggregation assay was designed and developed to detect abnormal tauaggregates in buffered solution or cell lysate by using anti-TauAPNmab005 as capture and detection antibody. This antibody is a highlyspecific antibody bound to human tau aggregates accumulated in mammaliancells. APNmAb005 is recited in PCT Patent Application No.PCT/M2020/057415, filed Aug. 5, 2020, which is incorporated herein byreference.

0.15 μg of APNmAb005 in 100 mM sodium carbonate buffer (pH 9.6) wascoated on a high-binding polystyrene 96-well microplate (GreinerBio-One) at 4° C. overnight. The microplate was washed with PBS followedby treatment with Intercept (PBS) blocking buffer (LI-COR) at roomtemperature for 2 hours. After that, the microplate was washed with PBS,and then the cell lysate with compound treatment, prepared as describedabove in step (C), was added into each well of the microplate andincubated at room temperature for 2 hours. The microplate was washedwith PBS and then incubated with HRP-conjugated secondary antibodyAPNmAb005 at room temperature for 3 hours. HRP-conjugated secondaryantibody APNmAb005 was prepared using HRP conjugation kit(Abcam,ab102890). The microplate was then washed with PBS and incubatedwith 100 μL of horseradish peroxidase (HRP) substrate at roomtemperature. After 20-min incubation, reactions were terminated byaddition of 100 μL of stop solution (Cell Signaling Technology). OpticalDensity (O.D.) at 450 nm was measured using EnVision microplate reader(PerkinElmer).

The FIGURE shows the degradation of Tau aggregates measured by APNmAb005ELISA assay. Upon treatment of 1 μM compound 162842, Optical Density(O.D.) 450 value decreases 20% compared to vehicle, reflecting thereduction of Tau aggregates.

Some embodiments of compounds were evaluated in Tau degradation assays.Results are summarized in Table 3.

TABLE 3 Compound Activity 170350 + 160219 − 160313 − 160744 + 171177 −161215 + 161409 + 160273 − 159985 − 162640 + 177031 − 162842 ++ 177038 −174251 − 162903 + 160939 − 163123 + 160383 − 163365 + Notes: “++”indicates >20% reduction of tau aggregates upon treatment with 1 μM ofcompound “+” indicates 10% to 20% reduction of tau aggregates upontreatment with 1 μM of compound “−” indicates <10% reduction of tauaggregates upon treatment with 1 μM of compound

Example 42: In Vivo Pharmacokinetic Study

To determine whether the compounds of the present disclosure are capableof crossing the blood brain barrier (BBB), example compound 160313 wasadministered to mice in a pharmacokinetic study (1 mg/kg, intravenous)of plasma and brain tissue.

Animal Husbandry: Mice were housed at animal room environment withventilation 15 times/hour, lighting 12 hours/day, temperature 20° C. to24° C. and humidity 40% to 70%. The study rooms were disinfected andcleaned prior to the start of the study and the operation area wascleaned after each dosing or sampling during the study conduct. Allanimals had free access to food and water during the study. The animalshad access to Certified Rodent Diet and water ad libitum. Thenutritional composition and levels of contaminants of the diet andimpurities and contaminants of the water were monitored by thirdorganization. The health status of the animals was evaluated inaccordance with accepted animal husbandry procedures and deemed suitablefor experimental use.

Sample Collection & Processing: Approximately 110 μL of whole blood werecollected from all animals via facial or cardiac puncture underanesthesia with Isoflurane into test tubes containing potassiumethylenediaminetetraacetate (K₂EDTA) at 0.25, 0.5, 1, 2, 4, 8 and 24 hrpost dose. Brian samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24hours post dose. A perfusion with pre-cold saline will be conducted viacardiac puncture before brain collection. Blood samples were centrifugedat 2000 g at 4° C. for 5 minutes to obtain plasma samples bytransferring the supernatants into new tubes. All plasma and brainsamples were stored at approximately −70° C. until analysis.

Bioanalytical Method Development: The concentrations of compound inplasma and brain samples were determined using a liquid chromatographywith tandem mass spectrometry (LC-MS/MS) based method.

Results: The PK parameters were summarized in Table 4. Compound 160313was able to penetrate BBB in short period of time. The brain/plasmaratio is about 0.31.

TABLE 4 In vivo pharmacokinetic profile of Compound 160313 Plasma BrainAUC_(last) (hr*ng/mL) 379 117 T_(1/2) (h) 0.46 1.03 C_(max) (ng/mL) —111 T_(max) (h) — 0.25

Certain embodiments are listed below.

Embodiment 1. A compound of Formula A,

EBM-L-TBM   (Formula A)

wherein

EBM is a ubiquitin E3 ligase binding moiety;

L is a linker covalently attached to EBM and TBM; and

TBM is a tau protein binding moiety of the formula:

or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, atautomer, a racemate, a solvate, a metabolic precursor, a prodrugthereof,wherein

is covalently linked to L; and

(i)

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; or

(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N.

Embodiment 2. The compound of Embodiment 1, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the substituted or unsubstituted bicyclic fused aromatic ring isa substituted or unsubstituted bicyclic 5-6 system.

Embodiment 3. The compound of Embodiment 1 or Embodiment 2, or thepharmaceutical acceptable salt, the enantiomer, the non-enantiomer, thetautomer, the racemate, the solvate, the metabolic precursor, or theprodrug thereof, wherein TBM is of Formula B or Formula C

wherein

Z is C or N; U is O, S or CH; V is N or NH;

K is CH or N; Q is CH or N; where K and Q are not N at the same time;

each occurrence of R′″ is independently selected from the groupconsisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy andhalogen; k is 0, 1, 2 or 3;

each occurrence of R′ is independently selected from the groupconsisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4;

each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl and C₃₋₆heterocycloalkyl; n is 0, 1 or 2;

J is CR⁶ or N; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J, Xand Y is N, but J and Y are not N at the same time, X and Y are not N atthe same time;

R⁶ is independently selected from the group consisting of H, NH₂, C₁₋₆alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo; and

in Formula B, V is N, where Z and U are not heteroatoms at the sametime; and

in Formula C, V is N or NH; T is CH or N; where up to two of U, Z, V andT contain heteroatoms.

Embodiment 4. The compound of any one of Embodiments 1-3, or thepharmaceutical acceptable salt, the enantiomer, the non-enantiomer, thetautomer, the racemate, the solvate, the metabolic precursor, or theprodrug thereof, wherein EBM is

wherein

R^(3′) is H or C₁₋₆ alkyl;

each occurrence of R^(2′) is independently selected from the groupconsisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and NH₂;

m6 is 0, 1, 2, 3 or 4; and

Y₁ is CH₂ or

Embodiment 5. The compound of any one of Embodiments 1-4, or thepharmaceutical acceptable salt, the enantiomer, the non-enantiomer, thetautomer, the racemate, the solvate, the metabolic precursor, or theprodrug thereof, of any one of Formula Ito Formula VI,

wherein,

L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group;

L₂ is a substituted or unsubstituted C₁₋₅₀ hydrocarbon chain, optionallywherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(a1)—, —S— or a cyclicmoiety, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group;

Z is C or N; U is O, S or CH;

K is CH or N; Q is CH or N; where K and Q are not N at the same time;

each occurrence of R′″ is independently selected from the groupconsisting of H, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy andhalogen; k is 0, 1, 2 or 3;

each occurrence of R′ is independently selected from the groupconsisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4;

each occurrence of R″ is independently selected from the groupconsisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl and C₃₋₆heterocycloalkyl; n is 0, 1 or 2;

J is CR⁶ or N; X is CR⁶ or N; Y is CR⁶ or N; where at least one of J, Xand Y is N, but J and Y are not N at the same time, X and Y are not N atthe same time;

R⁶ is independently selected from the group consisting of H, NH₂, C₁₋₆alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo;

in Formula I, L₃ is a bond, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; R^(3′) is H or C₁₋₆ alkyl;

Yi is CH₂ or

V is N, where Z and U are not heteroatoms at the same time;

in Formula II, each occurrence of R^(2′) is independently selected fromthe group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaminoand NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

V is N, where Z and U are not heteroatoms at the same time;

in Formula III, V is N, where Z and U are not heteroatoms at the sametime;

in Formula IV, L₃ is a bond, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

V is N or NH; T is CH or N; where up to two of U, Z, V and T containheteroatoms;

in Formula V, each occurrence of R^(2′) is independently selected fromthe group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylaminoand NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

V is N or NH; T is CH or N; where up to two of U, Z, V and T containheteroatoms;

in Formula VI, V is N; T is CH or N; where up to two of U, Z, V and Tcontain heteroatoms.

Embodiment 6. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is an optionally substituted C₁₋₄₅ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(a1)—, —S— or a cyclicmoiety, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group;

preferably, L₂ is a substituted or unsubstituted C₅₋₄₀ hydrocarbonchain;

preferably, L₂ is a substituted or unsubstituted C₁₋₃₀, C₁₋₂₄, or C₁₋₂₀hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1), —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group;

preferably, L₂ is an unsubstituted C₁₋₂₆, C₅₋₂₆, C₅₋₂₀, C₅₋₁₅, C₁₅₋₂₀,or C₂₀₋₂₅ hydrocarbon chain, wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O— or—NR^(a1)—, wherein R^(a1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl or a nitrogen protecting group.

Embodiment 7. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is an optionally substituted C₁₋₃₀ hydrocarbon chain, whereinone or more chain atoms of the hydrocarbon chain are independentlyreplaced with —O— or —NR^(a1)—, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group;

preferably, at least one chain atom of the hydrocarbon chain of L₂ isindependently replaced with —C(═O)—, —O—, —S—, —NR^(a1)—, —N═ or ═N—,wherein R^(a1) is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl or a nitrogen protecting group; preferably replaced with —O—.

Embodiment 8. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is selected from the group consisting of substituted orunsubstituted carbocyclylene, substituted or unsubstitutedheterocyclylene, substituted or unsubstituted arylene, substituted orunsubstituted heteroarylene, or substituted or unsubstitutedheteroalkylene, and combinations thereof;

preferably, L₂ is selected from the group consisting of substituted andunsubstituted alkylene, substituted and unsubstituted alkenylene,substituted and unsubstituted alkynylene, substituted and unsubstitutedheteroalkylene, substituted and unsubstituted heteroalkenylene,substituted and unsubstituted heteroalkynylene, substituted andunsubstituted heterocyclylene, substituted and unsubstitutedcarbocyclylene, substituted and unsubstituted arylene, substituted andunsubstituted heteroarylene, and combinations thereof.

Embodiment 9. The compound of Embodiment 8, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the carbocyclylene or the heterocyclylene is

Embodiment 10. The compound of Embodiment 8, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ comprises at least one instance selected from the groupconsisting of substituted or unsubstituted C₁₋₆ alkylene, substituted orunsubstituted C₂₋₆ alkenylene, substituted or unsubstituted C₂₋₆alkynylene, substituted or unsubstituted heteroC₁₋₆alkylene, substitutedor unsubstituted hetero C₂₋₆alkenylene, substituted or unsubstitutedhetero C₂₋₆alkynylene, substituted or unsubstituted C₃₋₆carbocyclylene,substituted or unsubstituted 3-6 membered heterocyclylene, substitutedor unsubstituted phenylene, and substituted or unsubstituted 5- to6-membered heteroarylene.

Embodiment 11. The compound of Embodiment 8, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ comprises at least one instance selected from the groupconsisting of substituted or unsubstituted methylene, ethylene,n-propylene, n-butylene, n-pentylene, n-hexylene, —(CH₂)₂—O(CH₂)₂—,—OCH₂—, —CH₂O—, —O(CH₂)₂—, —(CH₂)₂O—, —O(CH₂)₃—, —(CH₂)₃O—, —O(CH₂)₄O—,—(CH₂)₄O—, —O(CH₂)₅—, —(CH₂)₅O—, —O(CH₂)₆—, —O(CH₂)₆O—, —C(═O)O—,—O—C(═O)—, —NH—C(═O)— and 13 C(═O)NH—.

Embodiment 12. The compound of Embodiment 8, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein at least one chain atom of the hydrocarbon chain of L₂ isindependently replaced with a 6-membered heterocyclyl group with 1-3ring heteroatoms selected from the group consisting of nitrogen andoxygen;

preferably, at least one chain atom of the hydrocarbon chain of L₂ isindependently replaced with piperidine, piperazine or morpholine;

preferably, at least one chain atom of the hydrocarbon chain of L₂ isindependently replaced with an optionally substituted phenyl group.

Embodiment 13. The compound of Embodiment 8, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is an unsubstituted hydrocarbon chain, optionally wherein oneor more chain atoms of the hydrocarbon chain are independently replacedwith —NR^(a1)—, and each instance of R^(a1) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl or a nitrogen protecting group,or optionally two instances of R^(a1) are taken together with theirintervening atoms to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.

Embodiment 14. The compound of Embodiment 13, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein at least one instance of R^(a1) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl (e.g., substituted or unsubstituted methyl orethyl), or a nitrogen protecting group (e.g., benzyl, t-butyl carbonate,benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl,triphenylmethyl, acetyl or p-toluenesulfonamide).

Embodiment 15. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is

wherein g is 1, 2, 3, 4, 5, or 6.

Embodiment 16. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ includes the moiety —O—,

—NHC(═O)— or —NH—.

Embodiment 17. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein L₂ is selected from the group consisting of

wherein each g is independently 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5,or 6, and his 1, 2, 3, 4, 5, or 6.

Embodiment 18. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula I is of Formula I-1;

Embodiment 19. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula II is of Formula II-1;

Embodiment 20. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula III is of Formula III-1;

Embodiment 21. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula IV is of Formula IV-1;

Embodiment 22. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula V is of Formula V-1;

Embodiment 23. The compound of Embodiment 5, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula VI is of Formula VI-1;

Embodiment 24. The compound of Embodiment 18, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula I-1 is of Formula 1, 5, 6, 8, 10 or 13;

wherein

each A is independently O, NH,

m2 is 1, 2, 3, 4, 5, 6, or 7;

m3 is 1, 2, 3, 4, 5, or 6;

m4 is 0, 1, 2, or 3;

m5 is 0, 1, 2, or 3; and

R^(1′) is O, NH,

Embodiment 25. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 1, and wherein R′ is H, C₁₋₃haloalkyl or C₁₋₃ alkoxy; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino and C₃₋₅heterocycloalkyl; and/or, R′″ is H, OH or halogen; and/or, R^(1′) is O,NH,

and/or, A is O, NH,

and/or, m2 is 2, 3, 4 or 6; and/or, R^(3′) is H or C₁₋₃ alkyl.

Embodiment 26. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 5, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, each A is independently O, NH,

and/or, m4 is 0, 1, 2, or 3; and/or, m5 is 0, 1, 2 or 3; and/or, m3 is1, 2, 3, 4, 5 or 6; and/or, R^(1′) is O, NH or

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, R′ isH, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; and/or, m is0, 1, 2 or 3; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylaminoor C₃₋₅ heterocycloalkyl.

Embodiment 27. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 6, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH or

and/or, m2 is 1, 2, 3, 4, 5, 6 or 7; and/or, R^(1′) is O, NH or

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, R′ isH, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; and/or, m is0, 1, 2 or 3; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylaminoor C₃₋₅ heterocycloalkyl; and/or, n is 0 or 1.

Embodiment 28. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 8, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 1, 2, 3 or 4; and/or, R^(1′) is O, NH,

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, k is 0or 1; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃alkoxy; and/or, m is 0, 1 or 2; and/or, R″ is H, halo, OH, NH₂, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkylamino or C₃₋₅ heterocycloalkyl; and/or, n is 0, 1 or 2.

Embodiment 29. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 10, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, each A is independently O, NH,

and/or, m5 is 0 or 1; and/or, m4 is 0 or 1; and/or, m3 is 1, 2, 3, 4 or5; and/or, R^(1′) is O, NH,

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, k is 0or 1; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃alkoxy; and/or, m is 0 or 1; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₃₋₅ heterocycloalkyl; and/or, n is 0 or 1.

Embodiment 30. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 13, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 1, 2, 3 or 4; and/or, R^(1′) is O, NH,

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, R′ isH, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; and/or, m is0, 1, 2 or 3; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylaminoor C₃₋₅ heterocycloalkyl.

Embodiment 31. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula 1 is of Formula 1-1;

Embodiment 32. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula 5 is of Formula 5-1;

Embodiment 33. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound of Formula 6 is of Formula 6-1;

Embodiment 34. The compound of Embodiment 31, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(3′) is H or C₁₋₃ alkyl; A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 and 7; R^(1′) is O, NH,

R′ is H, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; R″ is H, F, Cl, OH, NH₂, C₁₋₃alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino.

Embodiment 35. The compound of Embodiment 32, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(3′) is H or C₁₋₃ alkyl; A is O, NH,

m5 is 0 or 1; m4 is 0, 1, 2, 3 or 4; m3 is 1, 2, 3, 4, 5 or 6; R^(1′) isO, NH,

R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; R′ is H, halogen, OH,C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; R″ is H, halo, OH, NH₂, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkylamino and C₃₋₅ heterocycloalkyl.

Embodiment 36. The compound of Embodiment 33, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(3′) is H or C₁₋₃ alkyl; A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 or 7; R^(1′) is O, NH,

R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; R′ is H, halogen, OH,C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; m is 0, 1, 2 or 3; R″ is H,halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃ alkylamino,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅ heterocycloalkyl.

Embodiment 37. The compound of Embodiment 24, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 1, 5, 6, 8, 10 or 13, and wherein Kis CH and Q is N, or K is N and Q is CH, or both of K and Q are CH.

Embodiment 38. The compound of Embodiment 19, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 3;

wherein R^(1′) is O, NH,

Embodiment 39. The compound of Embodiment 38, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylamino orNH₂; and/or, m6 is 0, 1, 2 or 3; and/or, R″ is 0 or NH; and/or, R′ is H,halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; and/or, R″ is H,halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino orC₁₋₃ alkylamino; and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy orhalogen.

Embodiment 40. The compound of Embodiment 38, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein Z is C and U is O or S; or Z is N and U is CH; and/or, K is CHand Q is N, or K is N and Q is CH, or both of K and Q are CH.

Embodiment 41. The compound of Embodiment 38, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 3-1;

Embodiment 42. The compound of Embodiment 41, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylamino orNH₂; m6 is 0, 1, 2 or 3; R″ is O, NH,

R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkylamino or C₁₋₃ alkylamino.

Embodiment 43. The compound of Embodiment 20, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 15;

wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R^(1′) is O, NH,

Embodiment 44. The compound of Embodiment 43, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and/or, R^(1′) is O, NH,

and/or, R′″ is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy or halogen; and/or, R′ isH, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy; m is 0, 1, 2or 3; and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₁₋₃ alkylamino.

Embodiment 45. The compound of Embodiment 21, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 2, 7, 9, 11, 12 or 14;

wherein

each A is independently O, NH,

m2 is 2, 3, 4, 5, or 6;

m3 is 1, 2, 3, 4, 5, or 6;

m4 is 0, 1, 2, 3, or 4;

m5 is 0, 1, 2, or 3; and

R^(1′) is O, NH,

Embodiment 46. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 2, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 2, 3, 4, 5 or 6; and/or, R^(1′) is O, NH,

and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl or C₁₋₃ alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H,OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 47. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 7, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 2, 3, 4, 5 or 6; and/or, R^(1′) is O, NH,

and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl or C₁₋₃ alkoxy; and/or, m is 0, 1, 2 or 3.

Embodiment 48. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 9, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 2, 3, 4, 5 or 6; and/or, R^(1′) is O, NH,

and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl or C₁₋₃ alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H,OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 49. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 11, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, A is O, NH,

and/or, m2 is 2, 3, 4, 5 or 6; and/or, R^(1′) is O, NH,

and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl or C₁₋₃ alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H,OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 50. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 12, and wherein R^(3′) is H or C₁₋₃alkyl; each A is independently O, NH,

m3 is 1, 2, 3, 4, 5 or 6; m4 is 0 or 1, 2 or 3; m5 is 0 or 1, 2 or 3;R^(1′) is O, NH,

R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, C₁₋₃alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl orC₁₋₃ alkoxy; m is 0, 1, 2 or 3; R′″ is H, OH, NH₂, C₁₋₃ alkyl, C₁₋₃alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 51. The compound of Embodiment 45, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 14, and wherein R^(3′) is H or C₁₋₃alkyl; and/or, each A is independently O, NH,

and/or, m3 is 1, 2, 3, 4, 5 or 6; and/or, m4 is 0, 1, 2, 3 or 4; and/or,m5 is 0 or 1, 2 or 3; and/or, R^(1′) is O, NH,

and/or, R″ is H, halo, OH, NH₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl,C₁₋₃ alkylamino, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkylamino or C₃₋₅heterocycloalkyl; and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl or C₁₋₃ alkoxy; m is 0, 1, 2 or 3; and/or, R′″ is H, OH, NH₂,C₁₋₃ alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 52. The compound of Embodiment 22, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 4;

wherein R^(1′) is O, NH,

Embodiment 53. The compound of Embodiment 52, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein R^(2′) is H, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ alkylamino orNH₂; and/or, m6 is 0, 1, 2 or 3; and/or, is O, NH,

and/or, R′ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl or C₁₋₃ alkoxy;R″ is H, halo, OH, NH₂, C₁₋₃ alkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylamino or C₁₋₃ alkylamino; and/or, R′″ is H, OH, NH₂, C₁₋₃alkyl, C₁₋₃ alkylamino, C₁₋₃ alkoxy or halogen.

Embodiment 54. The compound of Embodiment 52, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 4-1;

Embodiment 55. The compound of Embodiment 23, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 16 or 17;

wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R^(1′) is O, NH,

Embodiment 56. The compound of Embodiment 55, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 16, and wherein Z is C, U is O or Sand T is CH; or, Z is N, U is CH and T is CH; Z is C, T is N and U isCH.

Embodiment 57. The compound of Embodiment 55, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is of Formula 17, and wherein Z is C, U is O or Sand T is CH; or, Z is N, U is CH and T is CH; Z is C, T is N and U isCH.

Embodiment 58. The compound of Embodiment 1, or the pharmaceuticalacceptable salt, the enantiomer, the non-enantiomer, the tautomer, theracemate, the solvate, the metabolic precursor, or the prodrug thereof,wherein the compound is selected from the compound listed in Table 1.

Embodiment 59. A composition comprising, consisting essentially of, orconsisting of the compound of any one of Embodiments 1 to 58, or thepharmaceutical acceptable salt, the enantiomer, the non-enantiomer, thetautomer, the racemate, the solvate, the metabolic precursor, or theprodrug thereof, and a pharmaceutically acceptable excipient.

Embodiment 60. A composition comprising, consisting essentially of, orconsisting of the compound of any one of Embodiments 1 to 58, or thepharmaceutical acceptable salt, the enantiomer, the non-enantiomer, thetautomer, the racemate, the solvate, the metabolic precursor, or theprodrug thereof, and at least one pharmaceutically acceptable excipient.

Embodiment 61. A method for aiding in the treatment of a tauopathy ortreating tauopathy in a subject, comprising, consisting essentially of,or consisting of administering an effective amount of the compound ofany one of Embodiments 1 to 58, or the pharmaceutical acceptable salt,the enantiomer, the non-enantiomer, the tautomer, the racemate, thesolvate, the metabolic precursor, or the prodrug thereof, or thecomposition of Embodiment 59 to the subject.

Embodiment 62. A use of the compound of any one of Embodiments 1 to 58,or the pharmaceutical acceptable salt, the enantiomer, thenon-enantiomer, the tautomer, the racemate, the solvate, the metabolicprecursor, or the prodrug thereof, or the composition of Embodiment 59in the manufacture of a medicament for treating tauopathy.

What is claimed is:
 1. A compound of Formula A,EBM-L-TBM   (Formula A) wherein EBM is a ubiquitin E3 ligase bindingmoiety; L is a linker covalently attached to EBM and TBM; and TBM is atau protein binding moiety of the formula:

or a pharmaceutical acceptable salt, an enantiomer, a tautomer, aracemate, or a solvate thereof, wherein

is covalently linked to L; and (i)

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; or (ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0to 2 ring heteroatoms selected from O, S, and N; and

is a substituted or unsubstituted bicyclic fused aromatic ringcontaining at least 1 ring heteroatom selected from O, S, and N.
 2. Thecompound of claim 1, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe substituted or unsubstituted bicyclic fused aromatic ring is asubstituted or unsubstituted bicyclic 5-6 system.
 3. The compound ofclaim 1, or the pharmaceutical acceptable salt, the enantiomer, thetautomer, the racemate, or the solvate thereof, wherein TBM is ofFormula B or Formula C

wherein Z is C or N; U is O, S or CH; V is N or NH; K is CH or N; Q isCH or N; where K and Q are not N at the same time; each occurrence ofR′″ is independently selected from the group consisting of H, OH, NH₂,C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3;each occurrence of R′ is independently selected from the groupconsisting of H, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆alkoxy; m is 0, 1, 2, 3 or 4; each occurrence of R″ is independentlyselected from the group consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆cycloalkyl and C₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ or N; Xis CR⁶ or N; Y is CR⁶ or N; where at least one of J, X and Y is N, but Jand Y are not N at the same time, X and Y are not N at the same time; R⁶is independently selected from the group consisting of H, NH₂, C₁₋₆alkyl and C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy isoptionally substituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/orhalo; and in Formula B, V is N, where Z and U are not heteroatoms at thesame time; and in Formula C, V is N or NH; T is CH or N; where up to twoof U, Z, V and T contain heteroatoms.
 4. The compound of claim 1, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, wherein EBM is

wherein R^(3′) is H or C₁₋₆ alkyl; each occurrence of R^(2′) isindependently selected from the group consisting of H, OH, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ alkylamino and NH₂; m6 is 0, 1, 2, 3 or 4; and Y₁ isCH₂ or


5. The compound of claim 1, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, of anyone of Formula Ito Formula VI,

wherein, L₁ is a bond, —C(═O)—, —NR—, —O—, or —S—, wherein R ishydrogen, optionally substituted acyl, optionally substituted alkyl or anitrogen protecting group; L₂ is a substituted or unsubstituted C₁₋₅₀hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(a1)—, —S— or a cyclic moiety, wherein R^(a1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl or a nitrogenprotecting group; Z is C or N; U is O, S or CH; K is CH or N; Q is CH orN; where K and Q are not N at the same time; each occurrence of R′″ isindependently selected from the group consisting of H, OH, NH₂, C₁₋₆alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy and halogen; k is 0, 1, 2 or 3; eachoccurrence of R′ is independently selected from the group consisting ofH, halogen, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy; m is 0, 1,2, 3 or 4; each occurrence of R″ is independently selected from thegroup consisting of H, halo, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ alkylamino, C₃₋₆ cycloalkylamino, C₃₋₆ cycloalkyl andC₃₋₆ heterocycloalkyl; n is 0, 1 or 2; J is CR⁶ or N; X is CR⁶ or N; Yis CR⁶ or N; where at least one of J, X and Y is N, but J and Y are notN at the same time, X and Y are not N at the same time; R⁶ isindependently selected from the group consisting of H, NH₂, C₁₋₆ alkyland C₁₋₆ alkoxy, wherein NH₂, C₁₋₆ alkyl or C₁₋₆ alkoxy is optionallysubstituted by 1 to 3 of C₁₋₃ alkyl, C₃₋₆ cycloalkyl and/or halo; inFormula I, L₃ is a bond, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; R^(3′) is H or C₁₋₆ alkyl; Y₁ is CH₂ or

V is N, where Z and U are not heteroatoms at the same time; in FormulaII, each occurrence of R^(2′) is independently selected from the groupconsisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino and NH₂;m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

V is N, where Z and U are not heteroatoms at the same time; in FormulaIII, V is N, where Z and U are not heteroatoms at the same time; inFormula IV, L₃ is a bond, —NR—, —O—, or —S—, wherein R is hydrogen,optionally substituted acyl, optionally substituted alkyl or a nitrogenprotecting group; R³′ is H or C₁₋₆ alkyl; Y₁ is CH₂ or

V is N or NH; T is CH or N; where up to two of U, Z, V and T containheteroatoms; in Formula V, each occurrence of R^(2′) is independentlyselected from the group consisting of H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkylamino and NH₂; m6 is 0, 1, 2, 3 or 4; Y₁ is CH₂ or

V is N or NH; T is CH or N; where up to two of U, Z, V and T containheteroatoms; and in Formula VI, V is N; T is CH or N; where up to two ofU, Z, V and T contain heteroatoms.
 6. The compound of claim 5, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, wherein L₂ is an optionallysubstituted C₁₋₄₅ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═)—, —O—, —NR^(a1)—, —S— or a cyclic moiety, wherein R^(a1) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl or anitrogen protecting group.
 7. The compound of claim 5, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, wherein L₂ is selected from the groupconsisting of substituted or unsubstituted carbocyclylene, substitutedor unsubstituted heterocyclylene, substituted or unsubstituted arylene,substituted or unsubstituted heteroarylene, or substituted orunsubstituted heteroalkylene, and combinations thereof.
 8. The compoundof claim 7, or the pharmaceutical acceptable salt, the enantiomer, thetautomer, the racemate, or the solvate thereof, wherein L₂ comprises atleast one instance selected from the group consisting of substituted orunsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene,n-hexylene, —(CH₂)₂—O(CH₂)₂—, —OCH₂—, —CH₂O—, —O(CH₂)₂—, —(CH₂)₂O—,—O(CH₂)₃—, —(CH₂)₃O—, —O(CH₂)₄—, —(CH₂)₄O—, —O(CH₂)₅—, —(CH₂)₅O—,—O(CH₂)₆—, —O(CH₂)₆O—, —C(═O)O—, —O—C(═O)—, —NH—C(═O)— and —C(═O)NH—. 9.The compound of claim 7, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinat least one chain atom of the hydrocarbon chain of L₂ is independentlyreplaced with a 6-membered heterocyclyl group with 1-3 ring heteroatomsselected from the group consisting of nitrogen and oxygen.
 10. Thecompound of claim 7, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinL₂ is an unsubstituted hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—NR^(a1)—, and each instance of R^(a1) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl or a nitrogen protecting group,or optionally two instances of R^(a1) are taken together with theirintervening atoms to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.
 11. The compound of claim5, or the pharmaceutical acceptable salt, the enantiomer, the tautomer,the racemate, or the solvate thereof, wherein L₂ is

wherein g is 1, 2, 3, 4, 5, or
 6. 12. The compound of claim 5, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, wherein L₂ includes the moiety —O—,

—NHC(═O)— or —NH—.
 13. The compound of claim 5, or the pharmaceuticalacceptable salt, the enantiomer, the tautomer, the racemate, or thesolvate thereof, wherein L₂ is selected from the group consisting of

wherein each g is independently 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5,or 6, and his 1, 2, 3, 4, 5, or
 6. 14. The compound of claim 5, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, wherein the compound of Formula I isof Formula I-1;


15. The compound of claim 5, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound of Formula II is of Formula II-1;


16. The compound of claim 5, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound of Formula III is of Formula III-1;


17. The compound of claim 5, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound of Formula IV is of Formula IV-1;


18. The compound of claim 5, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound of Formula V is of Formula V-1;


19. The compound of claim 5, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound of Formula VI is of Formula VI-1;


20. The compound of claim 1, or the pharmaceutical acceptable salt, theenantiomer, the tautomer, the racemate, or the solvate thereof, whereinthe compound is selected from the group consisting of:


21. A composition comprising the compound of claim 1, or thepharmaceutical acceptable salt, the enantiomer, the tautomer, theracemate, or the solvate thereof, and at least one pharmaceuticallyacceptable excipient.
 22. A method for aiding in the treatment of atauopathy or treating tauopathy in a subject, comprising administeringan effective amount of the compound of claim 1, or the pharmaceuticalacceptable salt, the enantiomer, the tautomer, the racemate, or thesolvate thereof, to the subject.